EA020613B1 - Cytotoxic conjugates having neuropeptide y receptor binding compound - Google Patents

Abstract

There is provided a series of novel neuropeptide Y cytotoxic conjugates, compositions comprising the same, and methods relating to their therapeutic use for the treatment of disease or condition states associated with aberrant or undesirable proliferation of cells that express NPY-Y1 receptors.

Description

(57) The invention relates to groups of new neuropeptide Υ conjugates and cytotoxic compounds, compositions containing them and methods related to their therapeutic use for treating a disease or condition associated with impaired or undesired cell proliferation that express ΝΡΥ-Υ 1 receptors.

020 613 Β1

Technical field

The present invention relates to targeted cytotoxic compounds comprising a cytotoxic moiety linked to a guiding moiety, i.e. providing directional action of the connection. More specifically, the present invention relates to cytotoxic conjugates with neuropeptide Υ containing their compositions and methods related to their therapeutic use for the treatment of diseases or pathological conditions associated with impaired or undesirable cell proliferation, migration and / or physiological activity.

BACKGROUND OF THE INVENTION

Most cytotoxic drug compounds exhibit undesirable toxic side effects due to the lack of selectivity for tissues or cells that require a therapeutic effect. Various approaches have been taken to selectively deliver cytotoxic agents to the target cell type. The use of biological receptor ligands as carriers of drug compounds for the targeted delivery of these drug compounds to target cells can reduce toxic side effects and significantly increase the efficiency of drug delivery. For example, Patent Cooperation Treaty (PCT) Publication No. 97/19954 discloses conjugates of an anthracycline cytotoxic agent, such as doxorubicin, with a peptide hormone, such as BIRN, bombesin or somatostatin. The cytotoxic agent is covalently attached to the peptide via a linker having the structure —C (O) - (CH ₂ ) _P —C (O) -, in which n = 0-7.

Similarly, European Patent Application No. EP 1118336 discloses conjugates of somatostatin analogues, for example octreotide, lanreotide and vapreotide, and a cytotoxic drug compound such as paclitaxel, doxorubicin or camptothecin connected via a spacer, and it is indicated that the spacer has the structure-C (O) - (CH ₂ ) _p —C (O) -, in which p = 0-7.

US Patent Application Publication No. 2002/0115596 discloses conjugates of cytotoxic agents and oligopeptides in which the amino acid sequences of the peptides are cleaved preferably by a free prostatic specific antigen. It is claimed that such conjugates are suitable for the treatment of prostate cancer and benign prostatic hyperplasia.

US Patent Application Publication No. 2003/0064984 discloses conjugates of cytotoxic analogues of CC-1065 and duocarmycins with cleavable linker arms and a directing agent such as an antibody or peptide. Cytotoxic analogs are released upon linker cleavage.

PCT Publication AO 02/34237 discloses conjugates of active agents covalently attached directly to a polypeptide. The polypeptides are claimed to stabilize the active agent, for example, in the stomach, through conformational protection.

However, targeted cytotoxic drug compounds with improved properties with respect to targeted specificity, systemic toxicity and pharmacokinetics are still urgently needed.

The use of targeted cytotoxic compounds is believed to help treat a number of cancers or pathological conditions. For example, it is assumed that in the treatment of tumors or cancers that overexpress ней (ΝΡΥ) neuropeptide receptors, the directing and medicinal effects of the native human ней neuropeptide (ΗΝΡΥ), namely, N-Tug-Rgo-8eg-Eu8-Rgo-A8p, are used -A8p-Rgo-O1u-O1i-A8r-A1a-Rgo-A1a-O1i-A8r-Me1A1a-Ag§-Tug-Tug-§eg-A1a-Eee-Ag§-H18-Tug-11e-A8p-Eey- 11e-Thb-Arg-O1n-Arg-Tug-HH ₂ (8EC GO NO: 1), or a fragment or analog thereof, in complex with the cytotoxic part.

The ΝΡΥ effect can be mediated through several subtypes of ΝΡΥ-receptors called Υ1-Υ6, of which Υ1, Υ2, Υ4 and Υ5 are well described. For a review of ΝΡΥ and ΝΡΥ receptors, see, for example, S. Aai1e81eb1 apb Ό. Re18, Appia1 Be \ uh \ u o! Liao Taco, Apu Tojuo, 33: 309-352 (1993).

Based on the high density and high occurrence of the ΝΡΥ-Υ1 receptor in breast tumor samples and metastases, as described in PCT publication AO 02/43776, breast cancer is an important target for миш-linked drug compounds. It was also found (described in PCT publication AO 02/43776) that the Υ1 neuropeptide receptor is expressed exclusively in tumor tissue, either in combination with the Υ2 receptor, or separately, while only the Υ2 receptor is expressed in healthy tissue. The Υ1 receptor binding compound disclosed in PCT Publication AO 02/43776 is selected from the group consisting of the following compounds:

- 1 020613 [Ley ³¹ , Рgo ³⁴ ] -ΝΡΥ (3Εζ> Ιϋ N0: 81), [Ley ³¹ , Рgo ³⁴ ] -ΡΥΥ (ЗЕО

П> N0: 82), Рgo ^{3 4} -ΝΡΥ (ЗЕО ГО N0: 83), Рго ^31- РУ ¥ (ЗЕО ГО N0: 84),

ΝΡΥ (ZEO W N0: 1), ΡΥΥ (ZEO W N0: 80), Lee ARQ ²⁹ [Trp ^{28 '32, 34} Iua] ΝΡΥ (27-36) (Va1azigatapgat, RerbShez 18 (3), 445-457 (1997 ) (ZEO GO N0: 85)), [Рgo ³⁰ , Tug ³² , Leu ³⁴ ] -ΝΡΥ (28-36) (Lebap eb a1.,

L. Me <1. Eat. 38, 1150-1157 (1995) (ZEO GO N0: 86)), dimer ΒΪ5 (31/31 ¹ ) {[Suz ³¹ , Tgr ³² , No. / а ³⁴ ] -ΝΡΥ (31-36)} (Ba1azi gatapat, zirga , (ZEO GO N0: 87)), ZE120819A (ZeggyeN e a1, GEVZ 1ep.

225, 209-214 (1987)), ΒΙΒΡ3236 (Kis1o1 £ es a1, Eig. L,

Paganto 1. 271, K11-E13 (1994)), three compounds described in

Juap1 & 1st a1., Proc. Ba1. Asask 8c1. and 8A 92, 9067-9071 (1995}: 383 and 91 of the formula:

HerSuzRgoSuzTugATEYEYAtvtuaCHN}) I

NzMTugAgvyeiAgvTugSuzRgoSuzPe,

112 0H91 Formulas:

PyazaragooraTugAgeEeyAghhTugKTs

I

PeAhpRgoPraTugAgvyeiAgyTutMNg,

1229091 formulas

PeOiRGoRrGugat ^ BeyAgyyTugMNg

I I

ΗχΝΤγιΑΓΒΕβηΑΓβΤγιΟρΓΡΓοΟΙιιΠβ and arginine mimetics.

Thus, the ability of a compound to specifically interact with the ΝΡΥ-Υ1 receptor using Υ1-selective analogs of No. Υ conjugated to the cytotoxic part will contribute to the treatment of cancer diseases or conditions. Such cancers include, but are not limited to, breast cancer, ovarian cancer, glial tumors, renal cell carcinomas, nephroblastoma, and intratumoral blood vessels.

Particular advantages of the compounds of the present invention and their use as methods of treating tumors and cancers that are an important target of направленных-directed drug compounds include, but are not limited to, reduced toxic side effects, increased treatment efficacy, and / or less complications in the result of multidrug resistance.

SUMMARY OF THE INVENTION

In one aspect, the invention relates to targeted cytotoxic compounds with the following formula (I):

Χ-Β -Β ^{1 2 ϊ} -Β -Β ⁴ -Ζ (X) wherein X is a cytotoxic or cytostatic agent;

In ¹ represents τν (amino acid);

each of B ² , B ³ and B ⁴ , independently for each case, represents (Ooc) _m , (Aera) _n or -C (O) - ^ ¹ - ^ ² - ^ ³ - ^ ⁴ - ^ ⁵ -С (O) - or absent;

Ζ is a molecule that binds one or more subtypes of the ΝΡΥ receptor.

In the formula (I), Ζ is preferably an analog of ΗΝΡΥ. corresponding to the formula A ¹ -A ² -A ³ -A ⁴ -A ⁵ -A ⁶ -A ⁷ -A ⁸ -A ^E -A ¹⁰ -A ¹¹ -A ¹² -A ¹³ -A ¹⁴ -A ¹⁵ -A ^1b - A ¹ ' ⁷ -A ¹⁸ -A ^1E A ^2y -A ²¹ -A ²² -A ²³ -A ²⁴ -A ²⁵ -A ²⁶ -A ²⁷ -A ²⁸ -A ²⁹ -A ³⁰ -A ³¹ -A ³² -A ³³ -A ³⁴ -A ³⁵ -A ³⁶ -A ³⁷ -K ¹ (5E0 GO N0: 2), in which A ¹ represents Tug, (X ¹ , X ² , X ³ , X ⁴ , X ⁵ ) Pb or NH-SNTSNDrZhKSh'V-SHO);

And ² represents Rgo, 3Nur, s1k-3Nur, 4Nur or s1k-4Nur;

And ³ represents §et, Abi, Αί6, A1a, Tb or HX-CH ((CH ₂ ) _P- X (B ² K ³ )) - C (O);

And ⁴ represents Luk, Agd, LAtd, EaB, Er, Ogp or HX-CH ((CH ₂ ) _P -X (B ² K ³ )) - C (O);

And ⁵ represents Rgo, 3Nur, s18-3Nur, 4Nur or s1k-4Nur;

A ⁶ is Acre, A | b, Akp, 01p, 01i or HX-CH ((Sn ₂ ) _p -X (K ² K ³ )) - C (O);

A ⁷ represents Akp, A1b, 01p or HX-CH ((CH ₂ ) _P -X (K ² K ³ )) - C (O);

- 2,020,613

And ⁸ represents Rgo, 3Nur, s18-3Nur, 4Nur or s18-4Nur;

A ⁹ represents C1u, b or HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O);

And ¹⁰ represents s1i, Αί6, A8P, A8p, C1i or HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O);

A ¹¹ is A8p, AB, A8P, C1i, C1i or HX-CH ((CH ₂ ) _H- N (K ² K ³ )) - C (O);

A ¹² represents A1a, ABi, ASh, Ννα, Ya1 or HX-CH ((CH ₂ ) _H- N (K ² K ³ )) - C (O);

And ¹³ represents Rgo, 3Nur, s18-3Nur, 4Nur or s18-4Nur;

A ¹⁴ represents A1a, ABi, ASh, Ννα, Ya1 or HX-CH ((CH ₂ ) _H -X (K ² K ³ )) - C (O);

A ¹⁵ is C1i, A1b, A8P, A8p, C1i or HX-CH ((CH ₂ ) _H -X (K ² K ³ )) - C (O);

A ¹⁶ is A8p, A | b. A8P, C1i, C1i or HX-CH ((CH ₂ ) _H -X (K ² K ³ )) - C (O);

And ¹⁷ represents Me1, Ass, AB, Sl, 11e, Le, Le, Me, Lu, Tl, Wa1 or

NMSN ((CH2) _h- MK ² K ³ )) - C (O);

A ¹⁸ is A1a, ABi, ASh, Ννη, Ya1 or HX-CH ((CH ₂ ) _H- N (K ² K ³ )) - C (O);

And ¹⁹ represents Arg, bAgd, Are, OaB, Er, Li8, Ogp or HX-CH ((CH ₂ ) d-X (K ² K ³ )) - C (O);

And ²⁰ represents Tug, (X ¹ , X ² , X ³ , X ⁴ , X ⁵ ) Pb or HX — CH ((CH ₂ ) _H —X (K ² K ³ )) - C (O);

A ²¹ represents Tug, (X ¹ , X ² , X ³ , X ⁴ , X ⁵ ) Pb or HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O);

A ²² represents §eg, ABi, A1b, A1a, Tb or HX-CH ((CH ₂ ) _CH- K (K ² K ³ )) - C (O);

A ²³ represents A1a, ABi, ASh, Liu, Wa1 or HX-CH ((CH ₂ ) _H- Y (K ² K ³ )) - C (O);

And ²⁴ represents Ley, Ass, Sl, 11e, Ley, L1e, Lua, T1e, Ya1 or HX-CH ((CH2) H-S (K ² K ³ )) - C (O); And ²⁵ represents Arg, bAgd, EaB, Ear, bu8, Ogp or HX-CH ((CH2) _CH- S (K ² K ³ )) - C (O);

A ²⁶ represents H18, 2Pa1, 3Pa1, 4Pa1 or HX-CH ((CH ₂ ) _H- N (K ² K ³ )) - C (O);

And ²⁷ represents Tug, (X ¹ , X ² , X ³ , X ⁴ , X ⁵ ) Pb or HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O);

A ²⁸ is 11e, Ass, Cb, Le, Lb, Ll, Ll, Ll, Bal or HX-CH ((CH2) H-L (K ² K ³ )) C (O); A ²⁹ is A8n, AB, C1n or HX-CH ((CH2) _H- Y (K ² K ³ )) - C (O);

And ³⁰ is Ley, Ass, Sl, 11e, Ley, Ll, Ll, Ll, Ll or HX-CH ((CH2) H-L (K ² K ³ )) - C (O); And ³¹ represents 11e, Ass, Cb, Le, Lb, Ll, Ll, Ll, Ba1 or HX-CH ((CH2) _H- N (K ² K ³ )) - C (O); A ³² represents Tb, AB, 8eg or HX-CH ((CH ₂ ) _CH- K (K ² K ³ )) - C (O);

A ³³ represents Arg, bAgd, EaB, Ear, bu8, Ogp or HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O);

A ³⁴ represents C1n, A8n, Ep, 3Nur, s18-3Nur, 4Nur, s18-4Nur, 1pr, K1r, Nor, Oy, Prgo, Lrgo,

Tc or HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O);

A ³⁵ is Arg, A | c, Ars, bAgd, EaB, Ear, bu8, Ogp, 4kN ₂ Pb, 4kN ₂ CH ₂ Pb or HX-CH ((CH ₂ ) _H- K (K ² K ³ )) -C (O);

A ³⁶ is Tug, A1c, (X ¹ , X ² , X ³ , X ⁴ , X ⁵ ) Pb, HX-CH ((CH ₂ ) _H- K (K ² K ³ )) - C (O) or missing;

A ³⁷ represents HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O) or absent;

K ¹ represents OH, NH2, (C1-30) alkoxy or NH-X ⁶ -CH2-X ⁷ , where X ⁶ represents (C1-40) alkyl or (C2-40) alkenyl and X ⁷ represents H, OH, CO2H or C (O) -XH ₂ ;

each of V ¹ and V ⁵ , independently for each case, represents SC ⁴ K ⁵ ;

each of K ⁴ and K ⁵ , independently for each case, is H, P, Br, C1, I, (C _1-30 ) alkyl, (C _2-30 ) alkenyl, substituted (C _1-30 ) alkyl, substituted (C _2-30 ) alkenyl, 8K ⁶ , 8 (O) K ⁷ or 8 (O) 2K ⁸ or K ⁴ and K ⁵ together form (C3-30) cycloalkyl, (C _3-30 ) heterocyclic or (C _5-30 ) an aryl ring;

each of K ⁶ , K ⁷ and K ⁸ , independently for each case, is (C _1-30 ) alkyl, (C _2-30 ) alkenyl, substituted (C _1-30 ) alkyl or substituted (C _2-30 ) alkenyl;

each of V ² , V ³ and V ⁴ , independently for each case, represents SC ⁹ K ¹⁰ , O, 8, (CH ₂ ) ₁ or absent;

each of K ⁹ and K ¹⁰ , independently for each case, represents H, P, Br, C1, I, (C1-30) alkyl, (C2-30) alkenyl, substituted (C1-30) alkyl, substituted (C2 -30) alkenyl, 8K ⁶ , 8 (O) K ⁷ or 8 (O) 2K ⁸ or K ⁹ and K ¹⁰ together form a ring system;

t, independently for each case, is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n, independently for each case, is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; c |, independently for each case, represents 0, 1, 2, 3, 4 or 5;

1, independently for each case, is 0, 1, 2, or 3;

each of X ¹ , X ² , X ³ , X ⁴ and X ⁵ , independently for each case, is H, P, Br, C1, I, ( _C1-10 ) alkyl, substituted (C _1-10 ) alkyl, aryl, substituted aryl, OH, OMe, ΝΉ ₂ , NO ₂ or ΟΝ;

each of K ² and K ³ , independently for each case, is H, (C1-40) alkyl, (C1-40) heteroalkyl, (C1-40) acyl, (C2-40) alkenyl, (C2-40) alkynyl, aryl (C1-40) alkyl, aryl (C1-40) acyl, substituted (C1-40) alkyl, substituted (C1-40) heteroalkyl, substituted (C1-40) acyl, substituted (C2-40) alkenyl, substituted (C2-40) alkynyl, substituted aryl (C1-40) alkyl, substituted aryl (C1-40) acyl, (C1-40) alkylsulfonyl or C (XH) -CH2, wherein when K ² is (C1-40) ) acyl, aryl (C _1-40 ) acyl, substituted (C _1-40 ) acyl, substituted aryl (C _1-40 ) acyl, (C _1-40 ) alkylsulfonyl or C (CH) -YN ₂ , K ³ represents by itself H or ( _1-40) alkyl, (C _1-40) heteroalkyl, (C _2-40) alkenyl, (C _2-40) alkynyl, aryl (C _1-40) alkyl, substituted (S1-40) alkyl, substituted (C1 -40) heteroalkyl, substituted (C2-40) alkenyl, substituted (C _2-40 ) alkynyl or substituted aryl (C _1-40 ) alkyl.

- 3,020,613

The subtype (ΙΑ) of the compounds described by the above formula (I) includes compounds in which

X is a cytotoxic agent;

B ¹ represents τνΑδρ, τνΌ-Azr, r \ 'Sya, τνΌ-Sya or tuS1u;

In ² is Bis;

each of B ³ and B ⁴ , independently for each case, represents (Eos) _t . (Aera) _n or absent;

And ¹ represents Tug or HX-CH ((CH ₂ ) _H -X (K ² K ³ )) - C (O);

And ² represents Rgo;

And ³ represents Running, AB or HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O);

A ⁴ represents L3 or HX — CH ((CH ₂ ) _H —X (K ² K ³ )) —C (O);

And ⁵ represents Rgo;

And ⁶ represents Azr, A1b or HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O);

A ⁷ represents Azp, A1b or HX-CH ((CH ₂ ) _H —Y (K ² K ³ )) - C (O);

A ⁸ represents Rgo;

A ⁹ represents C1u, A1b or HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O);

A ¹⁰ represents C1i, A1b or HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O);

And ¹¹ represents Azr, AB or HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O);

A ¹² represents A1a, Λίό or HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O);

A ¹³ represents Rgo;

A ¹⁴ represents A1a, Λίό or HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O);

And ¹⁵ represents C1i, A1b or HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O);

And ¹⁶ represents Azr, AB or HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O);

A ¹⁷ is Me1, A6c, A1b, L1e or HX-CH ((CH ₂ ) _H -Y (K ² K ³ )) - C (O);

And ¹⁸ represents A1a, Λίό or HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O);

And ¹⁹ represents Agd or HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O);

And ²⁰ represents Tug or HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O);

A ²¹ Tug or NShSN ((CH ₂ ) _H- YUK ² K ³ )) - C (O);

A ²² is Running, A1b or HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O);

A ²³ represents A1a, Λίό or HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O);

And ²⁴ represents Ley, A6c or HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O);

A ²⁵ represents Agd or HX-CH ((CH ₂ ) _H —X (K ² K ³ )) —C (O);

A ²⁶ is C3 or HX-CH ((CH ₂ ) _H- B (K ² K ³ )) - C (O);

A ²⁷ represents Tug or HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O);

A ²⁸ is 11e, A6c, or HX-CH ((CH ₂ ) _H —Y (K ² K ³ )) —C (O);

A ²⁹ represents Azp, AB or HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O);

A ³⁰ is Ley, A6c or HX-CH ((CH ₂ ) _H —X (K ² K ³ )) —C (O);

A ³¹ represents 11e, A6c, Ley or HX-Sn ((Sn ₂ ) _h -Y (K ² K ³ )) - C (O);

A ³² represents Tyt, Λίό or HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O);

A ³³ represents Agd or HX-CH ((CH ₂ ) _H- S (K ² K ³ )) - C (O);

A ³⁴ is T1c, Air, 4Nur, Ιηρ, Νίρ, Prgo, bPto or HX-CH ((CH ₂ ) _H -X (K ² K ³ )) - C (O);

A ³⁵ represents Arg, Ac, Ars, L3, 4NH ₂ Pb, 4NH ₂ CH ₂ Pb or NCHS ((CH ₂ ) _H ^ (K ² K ³ )) - C (O);

A ³⁶ is Tug, Ac, NShSN ((CH ₂ ) _H- YUK ² K ³ )) - C (O) or absent;

And ³⁷ represents Н№СН ((СН ₂ ) _d -УК. ² К ³ )) - С (О) or absent;

K ¹ represents ΝΗ ₂ ;

each of K ² and K ³ , independently for each case, is H or (C1-30) acyl, provided that when K ² is (C1-30) acyl, K ³ is H;

each of K ⁴ and K ⁵ , independently for each case, is H or (C _1-40 ) acyl; c] represents 4;

each of X ¹ , X ² , X ³ , X ⁴ and X ⁵ , independently for each case, is Η, ί'ί ₂ ΝΗ ₂ or

ΝΗ ₂ .

In the formula (I) or subtype (1A), the peptide bond between A ³⁵ and A ³⁶ may be replaced by a pseudo-peptide bond in which A ³⁵ -A ³⁶ may be L3-ψ (CH ₂ -IN) Tyr or L3 ^ (CH ₂ -Yuas)) Here.

- 4,020,613

In a preferred embodiment, formula (I) or subtype (ΙΑ) Ζ corresponds to:

Example 1: [AL ¹⁰ , 4 Nur ³⁴ ] ΜΊΡΥ (136) -KH ₂ (ZEO BB N0: 3);

Example 2: [Αί®, 4Nur ³⁴ ] ΒΝΡΥ <1-36) -YN2 (ZEO GO N0: 4), Example 3: [AL ^11.17 , 4Ηγρ ³⁴ ] ΝΝΡΥ (1-36) -ΝΗ2 (ZEO ΙΌΝΟ: 5):

Example 4: [4Nur ³¹ ] LYRU (1-Zb) -IN ₂ (ZEO GO N0: 6);

Example 5: [AL ²² , 4 Nur ³⁴ ] LYRU (L-Zb) -YN ₂ (ZEO GO N0: 7);

4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ- ZEO GO N0: 8);

4Ηγρ ³⁴ ] ϊιΝΡΥ (1-36) -ΝΗ ₂ (ЗЕО 1Б N0: 9);

Example 6: [Abs Example 7: [Abs Example 8 [Abs, 4Ηγρ ³⁴ ] ΗΝΡΥ (1-36} -ΝΗ2 (ЗЕО Ш N0: Ю)? Example 9: [AL ³ , 4Nur ³⁴ ] ШРУ (1-36) -ΝΗ2 (ZEO Ιϋ N0: 11); Example 10: [Abs ²⁴ , 4Nur ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ2 (ZEO GO N0: 12); Example 11: [ΑίΒ ⁶ , 4Nur ³⁴ ] ЫРУ (1- 36) -MNg (Zeo GO ΝΟ: 13);

4Nur ³⁴ ] LYRU (1-Zb) -ΝΗ2 (ZEO GO N0: 14); 4Ηγρ ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ2 (ZEO GO N0: 15); 4Nur ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ2 (ZEO GO N0; 16); 4Nur ³⁴ ] ΙτΝΡΥ (1-36) -ΝΗ2 (ZEO GO N0: 17); 4Ηγρ ³⁴ ] ΝΝΡΥ (1-36) -ΝΗ2 (Zeo Yu ΝΟ: 18); 4Nur ³⁴ ] LYRU (1-36) -ΝΗ2 (ZEO 1B ΝΟ: 19); 4Ηγρ ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ2 (ZEO ΙΏΝΟ: 20); 4Ηγρ ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ2 (ZEO GO N0: 21);

Example 26: [Ax ¹¹ ',

Example 27: [At ^{10 '15,}

Example 121 (Az. ^1e Example 13: [ΑίΒ ²³ Example 14; [AL ³ ·

Example 15: [ΑίΒ ² '

Example 16: [Abs ¹ Example 17: [ΑίΒ ¹ Example 18: [ΑίΒ ¹ '

Example 19: [ΑίΒ ^1,

Example 20: [ΑίΒ ¹⁵ , 4 Nur ³⁴ ] LRU (1-36) -ΝΗ ₂ (ZEO GO N0: 22);

Example 21: [ΑίΒ ¹⁶ , 4Ηγρ ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ ₂ (ZEO 1B N0: 23);

Example 22: [AL ⁷ 4Nur ^34] YRU (1-Zb) ₂ -yn (ZEO GO N0: 24);

Example 23: [AL ⁹ , 4 Nur ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ ₂ (ZEO GO N0: 25);

Example 24: [AL ^{10 '17,} 4Ηγρ ^34] ΒΝΡΥ (1-36) -ΝΗ ₂ (ZEO GO N0: 26);

Example 25: [AL ¹⁵ · ¹⁷ , 4 Nur ³⁴ ] IYARU (1-36) -ΝΗ ₂ (ZEO SHI0: 27);

Νΐθ ¹⁷ , 4Ηγρ ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ2 (ZEO ΙΌ N0: 28); Νΐθ ¹⁷ , 4 Nur ³⁴ ) LNRU (1-Зb) -НН2 (ЗЕО Ю ИО: 29); 4Ηγρ ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ2 (ZEO ΙΟ N0: 30); 4Nur ³⁴ ) LYRU (1-36) -ΝΗ2 (ZEO GO N0: 31); 4Ηγρ ³¹ ] ΒΝΡΥ (1-36) -ΝΗ ₂ (ЗЕОГОЫО: 32);

4Nur ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ ₂ (ZEO GO N0: 33);

4Nur ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ ₂ (ZEO EB N0: 34);

[Al · ^{11 15 '17,} [Al ¹² · ¹⁵ · ¹⁷ [Al ^{10' 15 '17} [Al ¹¹ · ^16, [Al ¹⁰ · ¹⁶

Example 2-8: Example 29: Example 30: Example 31: Example 32:

Example 33: [AL ^{11 '17, 34} 4Nur, uz ³³ s (CH2 Chasse)) Τγτ ^36] ΗΝΡΥ (1-36) -ΝΗ2 (ZEO GO N0: 35), "", Ars ^35] MRU (1 -Zb) -YN ₂ (ZEO GO N0: 36);

, ALS ³⁶ ] LNRU (1-Zb) -YN ₂ (ZEO GO N0: 37);

411H ₂ Pbe ³³ ] ΗΝΡΥΙ1-36) -ΝΗ2 (ZEO GO N0: 38); 4ΝΗ2ΟΗ2ΡΗβ ³⁵ ] 1ιΝΡΥ (1-36) -ΝΗ2 (ZEO GO N0: 39);

Example 34: [AL ¹⁷ , 4Nur ³⁴ , Example 35: [AL ¹⁷ , 4Nur ³⁴ Example 36: [ΑίΒ ¹⁷ , 4Nur ³⁴ , Example 37: [AL ¹⁷ , 4Nur ³⁴ , Example 38: [AL ¹⁷ , 4Nur ³⁴ , Example 39: [AL ¹¹ · ¹⁷ . 4Nur ³⁴ Example 40: [Ley ³¹ , Rgo ³⁴ ,

Bk ³⁶ (H ^e -C (O) - (CH ₂ ) ₁₂ -CH ₃ )] ΜΠΎ (1- 36) -ΝΗ ₂ (ZEO GO N0: 42);

- 5,020,613

Example 41: [Ley ³¹ , Prgo ³⁴ , Luz ³⁵ (L'-C (O) - (CH ₂ ) 12-CH3)] ΗΝΡΥ (1-36) -TH ₂ (ZVD: Ιϋ N0: 43); Example 42: [Bf ³⁴ (S ^E —C (O) - (CH ₂ ) 12 — CH ₃ ), Ley ³¹ , Rgo ³⁴ ] LYRU (1-Zb) -IN ₂ (ZEO GO N0: 44); Example 43: [ly5 ²³ (s ^! -s (O) - (sn ₂ ) _12- sn ₃ ), iei ³¹ . Rgo ³⁴ ] Y1RU (1-Zb) -IN ₂ (3Ε0 ΐη N0: 45); Example 44: [Li5 ²² ( ^{L g} -C (O) - (CH ₂ ) ₁₂ -CH _e ), Ley ³¹ , Rgo ³⁴ ] LYRU (1- 36) -TH ₂ (5Ε0: ΕΌ N0: 46); Example 45: [L3 ³¹ (1, H-C (O) - (CH ₂ ) ₁₂ -CH,), Ley ³¹ , Ργο ³⁴ ]] ίΝΡΥ (1- 36) -TH ₂ (ΞΕ <2 Ιϋ N0: 47) Example 46: [Ls ²⁰ ( ^{L g} -C (O) - (CH ₂ ) 12-CH3), Ley ³¹ , Rgo ³⁴ ] MYARU <1- 36) -UN ₂ (ΞΕΩ ΙΌ N0: 48); Example 47: [Ls ¹⁵ (H ^E — C (O) - (CH ₂ ) 12 — CH ₃ ), Ley ³¹ , Rgo ³⁴ ] Y4RU (1- 36) -YN ₂ (3Ε0 ΙΠ N0: 49}; Example 48: [Bk ¹³ (And ⁵ -C (O) - (CH ₂ ) 12-Cb), Ley ³¹ , Рgo ³⁴ ] ΠΝΡΥ (1 - 3 6) -IN ₂ (ZVD ΙΟ N0: 50); Example 49: [Bk ¹⁷ (S ^E -C (O) - (CH ₂ ) ₁₂ -CH3), Ley ³¹ , RGS? ⁴ ] Y-1RU (1- 36) -IN ₂ (ΞΕΟ ΙΏ N0: 51); Example fifty: [Bf ¹⁶ (bf C (0) - (0¾) ₁₂ C * H ₃ ), Ley ³¹ , Рgo ³⁴ 1ЬЫРУ (1- 36) -ΝΗ ₂ (3Ε0 ΙΟ N0: 52), Example 51: [bk ¹⁵ (Ν'-C (O) - (CH ₂ ) 12-CH3,, Ley ³¹ , Ργο ³⁴ ] ΗΝΡΥ (1- 36) -ΝΗ ₂ (3Ε0 ΙΏ N0: 53); Example 52: [Ls ¹⁴ ( ^{L g} -C (O) - (CH ₂ ) 12-CH ₃ ), Ley ³¹ , rgo ³⁴ ] Llru (1-zb) -yn ₂ (3Ε0 ΙΏ N0: 54} Example 53: [Li3 ¹² (KG-C (O) - (CH ₂ ) ₁₂ -CH3), Ley ³¹ , Ργο ³⁴ ]] ίΝΡΥ (1- 36) -ΝΗ ₂ (3Ε0 ΙΠ N0: 55), Example 54: [Bb ¹¹ ( ^{B E} -C (0) - (CH ₂ ) ₁₂ -CH3), Ley ³¹ , Ργο ³⁴ ] ΚΝΡΥ (1- 36) -ΝΗ ₂ (5Ε0 ΙΌ N0: 56); Example 55: [B3 ¹⁰ (S'-C (O) (CH ₂ ) ₁₂ -CH3), Ley ³¹ , Rgo ³⁴ ] LYRU (1- 36) -ΝΗ ₂ (3Ε0 Ιϋ N0: 57) Example 56: [Bk ⁹ <N '- <3 (0) - (CH ₂ ) ₁₂ -CH3), Ley ³¹ , Rgo ³⁴ ] LNRU (1- 36) -ΝΗ ₂ (3Ε0 ΙΏ N0: 58); Example 57: [Bb ⁷ (b'-c (O) - (CH ₂ ) ₁₂ -CH3), Ley ³¹ , рго ³⁴ ] ммру (1- зб) -мн ₂ (3Ε0 ΙΟ N0: 59); Example 58: [Bk ⁶ (Ν'-C (O) - (CH ₂ ) 1 ₂ -CH3), Ley ³¹ , Ργο ³⁴ ] 1ϊΝΡΥ (1- 36) -ΝΗ ₂ (5VD ΙΏ N0: 60) Example 59: (Ls ⁴ (L'C (O) - (CH ₂ ) ₁₂ -CH3), Ley ³¹ , Ργο ³⁴ ] 1ιΝΡΥ (1- 36) -ΝΗ ₂ (3Ε0 ΙΌ N0: 61)! Example 60: [L3 ³ (S'-C (O) - (CH ₂ ) 12-CH3), Ley ³¹ , ργο ³⁴ ] Ημρυ (1- зб) -н ₂ (ΞΕ0 Ιϋ N0: 62) Example 61: [Bf ¹ (SG-C (O) - (CH ₂ ) 12-CH ₃ ), Ley ³¹ , Ργο ³⁴ ] 1ιΝΕΥ <1-36) -ΜΗ ₂ (5Ε0 ΙΏ N0: 63),

Example 62: [Ley ³¹ , Rgo ³⁴ , Luke ³⁷ (Ϊ-Τ-Ο (Ο) (CH ₂ ) ₁₂ -CH ₃ )] 1ιΝΡΥ (1-37) -ΝΗ ₂ (Zeo ιό: N0: 64); Example 63: [Ley ³¹ , Luke ³³ (s ^r -C (O) - (cn ₂ ) 1 ₂ - SNS), ργο ³⁴ ] 1ίνρυ (1-3 6) -νη ₂ (Zeo ΙΌ N0: 65); Example 64: [Ley ³¹ , Luke ³² (1 ^ -0 (0) - (0¾) 12- DSC), ργο ³⁴ ] Ηνρυ (1- 36) -νη ₂ (Zeo 10 N0: 66); Example 65: [Uz ³¹ (N-C (O) - (CH _{2) 3} CH-1d) Ρτο ³¹ ] 1ιΝΡΎ (1-36) -ΝΗ ₂ (ZEO GO N0: 67), Example 66: [LU ³ "(S ^E -C (O) - (CH ₂ ) ₁₂ -CH ₃ ), Ley ³¹ , Rgo ³⁴ ] Shru (1- 36) -ΝΗ ₂ (Zeo 1B N0: 68); Example 67: [Ls ²⁹ (Ν'-C (0) - (CH ₂ ) 12-CH 3), Ley ³¹ , Ργο ³⁴ ] ΗΝΡΥ (1- 36) -ΝΗ ₂ (Zeo ΙΏ N0: 69) Example 68: [Ls ²⁸ (L ¹ —C (O) - (CH ₂ ) 1 ₂ —CH ₃ ), Ley ³¹ , Rgo ³⁴ ] LYRU (1- 36) -ΝΗ ₂ (Zeo ΙΌ N0: 70) Example 69: [Bf ²⁷ W ^E -C (0) - (CH ₂ ) i-CH3), Ley ³¹ , Rgo ³⁴ ] LYRU (1- 36) -ΝΗ ₂ (Zeo ΙΟ N0: 71) Example 70: [Lb ²⁶ (L ^e -C (O) - (CH ₂ > 12-CH 3), Ley ³¹ , Rgo ³⁴ ] NYKG (1- 36) -ΝΗ ₂ (Zeo w N0: 72) Example 71: [Ls ²⁵ ( ^{L E} —C (O) - (CH ₂ ) 12 — CH ₃ ), Ley ³¹ , Rgo ³⁴ ] LMPU (1- 36) -ΝΗ ₂ (Zeo Yu N0: 73) Example 72: [Νίρ ³⁴ ] 1ιΝΡΥ (1-36) -ΝΗ ₂ (Zeo Yu N0: 74); Example 73: ΙΙηρ ³⁴ ] 1ιΝΡΥ (1-36) -ΝΗ ₂ (Zeo Ιϋ N0: 75); Example 74: [Y1p ³⁴ ] yyru (1-zb) -νη _{2 of} both N0: 76); Example 75: [M> go ³⁴ ] YYRU (1-36) -ΝΗ ₂ (ZEO GO N0: 77); Example 76: [T1C ³⁴ ] YYRU (1-36) -IN ₂ (Zeo GO N0: 78); Example 77: [Ley ³¹ , Luke ³⁴ (M ^E -C (O) - (CH ₂ ) 12 -CH ₃ )] LYRU (1-Zb) -ΝΗ ₂ (Zeo Ιϋ N0: 79); Example 78: ΝΡΥ-ΝΗ ₂ (ZEO GO N0: 1); Example 79: ΡΥΥ-ΝΗ2 (ZEO GO N0: 80);

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Example 80: (Pei ³¹ , Rgo ³⁴ ] -ΝΡΥ-ΝΗ ₂ (Zeo ΙΠΝ0.-81); Example 81: [Lei ³¹ , Prgo ³⁴ ] -ΡΥΥ-ΝΗ ₂ (Zeo ΙΌΝΟ: 82); Example 82: [Рgo ³⁴ ] -ΝΡΥ-ΝΗ ₂ (ЗЕО П> НО: 83); Example 82A: [Рgo ³⁴ ] -ΡΥΥ-ЕНг (ЗЕО ΙΏ НО: 84); Example 83: Without Aep. ²⁹ [Trp ^{23 '32, 34} Yua] -ΝΡΥ (27-36) -YN ₂ (ZEO Yu N0: 85); Example 84: [Rgo ³⁰ , Tug ³² , Ley ³⁴ ] -ΝΡΥΙ28-36) -TH ₂ (ZEO HUMO: 86); Example 85: dimer B ± d (31/31) {[Court ³¹ , Tgr ³² , No. / a ³⁴ ] -ΝΡΥ (31-36) -NY ₂ > (ZEO UYO: 87) Example 86: 5K120819A; Example 87: ΒΙΒΡ3236; Example 88: compound 383X191 of the formula:

PesuzRtoSuzTugAgayeiAgvTugMN!

NaotugAgvyeiAgvTugSuzRyuSuzPe,

Example 89: compound 1120I91 of the formula:

IeAZargoPraTugAgeSiAgvTutGN!

I

PeA $ pRGoPraTugA1 £ L1 | A1 £ 1Y | No. 12, _

Example 90: compound 1229I91 of the formula:

PSU1IRGO> RNTUGATVIEVAAg8TugMN ₂ II

I ^>> Tu1A | bSiA1 ^ GuFr11 ^> n> C1i1b or

Example 90A: [CH ₃ (CH ₂ ) ₈ (CO) -Tug ¹ , L1e ¹⁷ , Prgo ³⁴ ] TPU (1-36) -IN ₂ (ZEO ΙΟ ΝΟ: 105).

Another subtype (ΙΒ) of the compounds described by formula (I) or a subtype (ΙΑ) are compounds in which:

A ¹ is Tug;

A ³ represents §et;

And ⁴ represents Luke;

A ⁶ is Acre;

A ⁷ is Akp;

A ⁹ is C1u;

A ¹⁰ is C1i;

A ¹¹ represents Acre;

A ¹² is A1a;

A ¹⁴ is A1a;

A ¹⁵ is C1i;

A ¹⁶ represents Acre;

A ¹⁷ is AB or L1e;

A ¹⁸ is A1a;

A ¹⁹ is Hell;

A ²⁰ is Tug;

A ²¹ represents Tug;

A ²² represents §et;

A ²³ represents A1a;

A ²⁴ represents Ley;

A ²⁵ represents Agd;

A ²⁶ is Ηίκ;

A ²⁷ is Tug;

A ²⁸ is 11e;

A ²⁹ represents Akp;

A ³⁰ is lei;

A ³¹ is 11e or A6c;

A ³² is Tyt;

A ³³ represents Agd;

A ³⁴ represents 4Nur or Rgo;

A ³⁵ is Agd or Ac;

A ³⁶ is Tug, Ac or absent;

A ^{37 is} missing.

- 7,020,613

A preferred embodiment of the present invention is a compound of formula (I), a subtype (ΙΑ) or subtype (ΙΒ), wherein X is anthracycline, camptothecin, camptothecin derivative, paclitaxel, paclitaxel derivative, doxorubicin or doxorubicin derivative.

In a further preferred embodiment of the present invention, X is camptothecin or a camptothecin derivative, wherein said camptothecin derivative is:

or X is paclitaxel or a paclitaxel derivative, said paclitaxel derivative being

or X is doxorubicin or a doxorubicin derivative, wherein said doxorubicin derivative is

- 8,020,613

A further preferred embodiment of the invention is any one of the following compounds of subtype (1B):

4Ηγρ ^{! 4} ] ϊιΝΡΥ (1-36) -ΝΗ ₂ (ZEO GO N0: 91);

Example 95: [camptothecin-guO-Aar-Zis-Tug ¹ , Νΐθ ¹⁷ ,

Рgo ³⁴ ] Μ-ΙΡΥ (1-36) -IN ₂ ;

Example 95A: [camptothecin-guAzr-Zis-Tug ¹ , H1e ¹⁷ ,

Rgo ³⁴ ] ShRU (1-36) -IN ₂ (ZEO GO N0: 92);

Example 96: [camptothecin-gusa-Zys-Tug ¹ , Mlie ¹⁷ , Prgo ³⁴ ] LYRU (136) -KSH ₂ (ZEO GO N0: 93);

Example 96A: [camptothecin-guO-CAB-Zys-Tug ¹ , L1e ¹⁷ ,

Рgo ³⁴ ) Ы1РУ (1-36) -ΝΗ ₂ ;

Example 97: [camptothecin-guSXu-Zis-Tug ¹ , 1 <1e ¹⁷ ,

4Nur ³⁴ ] ShR ¥ (1-Zb) -MN ₂ (Zeo Yu N0: 94);

Example 98; [camptothecin-guC1u-5is- (Juos) s-Tug ¹ , 1T1e ¹⁷ , 4Nur ³⁴ 1ShRU (1-36) -MN ₂ (ZEO GO N0: 95);

Example 99: [camptothecin-guO1u-5is- (ϋοο) ₃ -Aera-Tug ³ , G'Pe ' ⁷ , 4Nur ³⁴ ] SHRU (1-36) -ΝΗ ₂ (ZEO GO N0: 96);

Example 100: Ekamptothecin-guO-Azr-Zis- (Pos) ₂ Tug ¹ , Νίβ ¹⁷ ,

4Ηγρ ³¹ ] ΝΝΡΥ (1-36) -ΝΗ ₂ ;

Example 100A: [camptothecin-guAzr-Zis- (NYUS) s-Tug ¹ , Νΐθ ¹⁷ ,

4Nur ^m ] 1MRU (1-36) -M (ZEO GO N0: 97);

Example 101: [camptothecin-guC1u-5is-Aera- (E> oc) s-Tug ¹ , Li1e ¹⁷ , 4Nur ^and ] 1JuT ¥ (1-Zb) -N (ZEO GO N0: 98);

Example 102; [camptothecin-guR-Aer-Zis- (Bos) s-Aera-Tug ¹ L1e ¹⁷ , 4Nur ³⁴ ] SHRU (1-36) -IN ₂ ;

Example 102A; [camptothecin-guAzr-Zis- (Ros) s-Aera-Tug ¹ , Ly1e ¹⁷ , 4Nur ³¹ ] ΝΝΡΥ (1-36) -NY ₂ (ZEO GO N0: 99);

Example 103: [camptothecin-guR-Azr-Zis-Aera- (Ros) s-Tug ¹ ,

L1e ¹⁷ , 4Nur ³¹ ] 1ΝΡΥ (1-36) -ΝΗ ₂ ;

Example of SWA: [camptothecin-guAzr-Zis-Aera- (Ros) s-Tug ¹ ,

L1e ¹⁷ , 4Nur ^m ] ΜΜΡΥ (1-36) -ΝΗ ₂ (ZEO GO N0: 100);

Example 104: [camptothecin-guOJAu-Zis-Tug ¹ , Axb ¹⁷ , 4 Nur ³⁴ ,

36ο ³⁶ ] 1ιΝΡΥ (1-36) -ΝΗ ₂ (ZEO GO N0: 101);

Example 105: [camptothecin-lip Lu-Zis-Tug ¹ , ΑίΧ> ¹⁷ , 4 Nur ³⁴ ,

Ad.s ³⁵ ] NL> ¥ (1-35) -IN ₂ (ZEO GO N0: 102);

Example 106; [camptothecin-guC1u-5is- (Ros) s-Tug ¹ , ΑΐΡ ¹⁷ ,

4Nur ³⁴ , Αίο ^3ί ] 1ιΝΡΥ (1-36) -KI ₂ (ZEO GO N0: 103) and

Example 107; [camptothecin-g \ L31u-5is-Aera- (Oos) ₃ Tug ¹ , ΑίΡ ¹⁷ , 4 Nur ³⁴ , A1s ³⁶ ) LYRU (1-36) -ΝΗ ₂ (5Е0 Ю N0: 104),

Example 108: [ЗпЗб-гУСХу-Зис-Туг ¹ , Н1е ¹⁷ , Ργο ³⁴ ] 1ιΝΡΥ (1-36) ΝΗ ₂ (ЗЕО ГО N0: 88);

Example 109: [ZpZb-guAzr-Zis-Tug ¹ , Νΐθ ¹⁷ , 4Nur ³⁴ ] ΠΝΡΥ (1-36) ΝΗ ₂ (ZEO GO N0: 89) or

Example 110: [ZpZv-guAar-Zis-Tug ¹ , Νίβ ¹⁷ , Abs ³¹ ,

4Nur ”] 11ΝΡΥ (1-36) -ΝΗ ₂ (ZEO GO N0: 90) or a pharmaceutically acceptable salt thereof.

- 9,020,613

In an additional aspect, the invention relates to a mixture of compounds of formula (I), a subtype (ΙΑ) or subtype (GW), in which the linker τν (amino acid) is in the Ό-form in some compounds in the mixture and in the L-form in some compounds in the mixture . The mixture includes (by weight) about 2:98, about 5:95, about 10:90, about 15:85, about 20:80, about 25:75, about 30:70, about 35:65, about 40 : 60, about 45:50, about 50:50, about 55:45, about 60:40, about 65:25, about 70:30, about 75:25, about 80:20, about 85:15, about 90 : 10, about 95: 5, about 97: 3, or even about 98: 2 compounds in a mixture in which the linker τν (amino acid) is in the форме-form and in the форме-form, respectively.

Brief Description of the Drawings

In FIG. 1 shows the tumor growth median curves for the compounds of Example 91, which show the ίη νίνο effects of the compound of Example 91 in three different dosages on the median tumor growth in Study A compared to the absence of treatment or treatment with camptothecin alone.

In FIG. Figure 2 shows the tumor growth median curves for the compounds of Example 92, which show the ίη νίνο effects of the compound of Example 92 in three different dosages on the tumor growth median in Study A compared to the absence of treatment or treatment with camptothecin alone.

In FIG. Figure 3 shows the tumor growth median curves for the compounds of Example 93, which show the ίη νίνο effects of the compound of Example 93 at three different dosages on the tumor growth median in Study B compared to the absence of treatment or treatment with camptothecin alone.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term amino acid refers to any naturally occurring or unnatural amino acid, including, but not limited to, α-amino acids, β-amino acids or γ-amino acids, and it can refer to either либо- or b-amino acids, if not indicated otherwise.

With the exception of the Ν-terminal amino acid, all amino acid abbreviations (eg, A1a) in this description have the structure -ΝΗ-ί'.Ί (Β ') - ί'.Ό-. in which K and K ¹ each independently represent hydrogen or an amino acid side chain (for example, K = CH ₃ and K '= H for A1a), or K and K' can be connected to form a ring system.

The peptide of this invention is also designated using a different format, for example [Ρτο ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ ₂ (Betz ΙΌ ΝΟ: 83), with substituted amino acids from the natural sequence placed in square brackets, for example, Rgo instead of Ο1η in ΙιΝΡΥ. The designation ΝΗ ₂ in ΗΝΡΥ (1-36) -ΝΗ ₂ (CEC ΙΌ ΝΟ: 1) indicates that the C-terminus of the peptide is amidated, while ΗΝΡΥ (1-36) -ΟΗ (CEC ΙΌ ΝΟ: 1) indicates free acid.

For convenience, the following is a list of some of the abbreviations used in this application, however, any abbreviation used in this application, the definition of which is not given therein, is not used in a value that contradicts the generally accepted.

AI - α-aminobutyric acid

Ace - 1-amino-1-cyclo (C _3-9 ) alkylcarboxylic acid, wherein

A3c is 1-amino-1-cyclopropanecarboxylic acid;

A4c is 1-amino-1-cyclobutanecarboxylic acid;

A5c is 1-amino-1-cyclopentanecarboxylic acid;

A6c is 1-amino-1-cyclohexanecarboxylic acid;

Abs - 10-aminodecanoic acid;

Αάο - 12-aminododecanoic acid;

Aera - 4- (2-aminoethyl) -1-carboxymethylpiperazine represented by the structure Acre - 7-aminoheptanoic acid;

Ax - 6-aminohexanoic acid;

AB is α-aminoisobutyric acid;

Ac - 2-aminoindan-2-carboxylic acid;

A1a or A is alanine;

Abs - 9-aminononanoic acid;

Αοс - 8-amino-octanoic acid;

Ars is 4-amino-4-carboxypiperidine represented by structure ⁰ — wherein parallel lines = indicate points of attachment of the molecule to another molecule or sequence;

Arp - 5-aminopentanoic acid;

Agd or K - arginine;

LADD - homoarginine;

Akp or Ν - luorenilm;

- 10,020,613

Acre or Ό - aspartic acid;

Aip - 11-aminoundecanoic acid;

CHA - β-cyclohexylalanine;

Bitch or C is cysteine;

EaB - 2,4-diaminobutyric acid;

Air - 2,3-diaminopropionic acid;

ENR - 3,4-dehydroproline;

From! - 5,5-dimethylthiazolidine-4-carboxylic acid;

that about t “,,

Loe - 8-amino-3,6-dioxaoctanoic acid represented by the structure '· -;

CaLa - 4-aminobutyric acid;

C1p or O - glutamine;

C1i or E - glutamic acid;

C1u or C is glycine;

Ηίκ or H is histidine;

3Nur is trans-3-hydroxy-L-proline, i.e. (25.35) -3-hydroxypyrrolidine-2-carboxylic acid; C18-3Nur is cis-3-hydroxy-L-proline, i.e. (25.35) -3-hydroxypyrrolidine-2-carboxylic acid; 4Nur - 4-hydroxyproline, i.e. (2§, 4K) -4-hydroxypyrrolidine-2-carboxylic acid;

C18-4Nur is cis-4-hydroxy-L-proline, i.e. (25.45) -4-hydroxypyrrolidine-2-carboxylic acid; 11e or I - isoleucine;

1ps - indoline-2-carboxylic acid;

1pr - isonipecotinic acid;

Κίρ is 4-ketoproline;

Bey or b - leucine;

Ley - homoleucine;

Buc or Κ is lysine;

Me! or M is methionine;

No. p - nipecotinic acid;

Me - norleucine;

Ν ^ε indicates that the structure in parentheses is attached to the epsilon-nitrogen of the Luc side chain; Νν; · ι - norvaline;

01c - octahydroindole-2-carboxylic acid;

Ogp - ornithine;

2- Ra1 - b- (2-pyridyl) alanine;

3- Ra1 - b- (3-pyridyl) alanine;

4- Ra1 - b- (4-pyridyl) alanine;

RNe or P - phenylalanine;

НРНе - homophenylalanine;

4MH ₂ CH ₂ RNe - 4-aminomethylphenylalanine;

4ΝΗ ₂ Ρ1β; - 4-aminophenylalanine;

Рgo or Р - proline;

NRgo - homoproline;

5ag - sarcosine or Ν-methylglycine;

5eg or δ is serine;

About _{δ th}

5is — succinyl represented by o;

TNG or T-threonine;

T1C - 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;

T1e - tert-leucine;

Va1 or V - valine.

The following is a definition of other abbreviations used in this document: Ac - acetyl;

A1oC - allyloxycarbonyl;

Boc is tert-butyloxycarbonyl;

VNOS - benzhydryloxycarbonyl;

ΒδΑ - bovine serum albumin;

Βζ1 is benzyl;

CPT - camptothecin;

ESM - dichloromethane;

Both are 1- (4,4-dimethyl-2,6-dioxocyclohex-1-ylidine) ethyl;

E1C - Ν, Ν-diisopropylcarbodiimide;

- 11,020,613

ΌΙΕΑ - diisopropylethylamine;

ΌΜΆ - Ν, Ν-dimethylacetamide;

OTAL - 4- {A- (1- (4,4-dimethyl-2,6-dioxocyclohexylidene) -3-methylbutyl) amino} benzyl; ΌΜΑΡ - 4- (dimethylamino) pyridine;

ΌΜΡ - dimethylformamide;

ΌΝΡ - 2,4-dinitrophenyl;

Ό5 \ ν - 5% solution of dextrose in water;

ΕΌΟ - 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride;

C1 is ethyl;

ΕΜΕΜ - minimum supporting environment Needle;

RTOS is fluorenylmethoxycarbonyl;

NATI - O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate;

NVTI - 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate; cNex - cyclohexyl;

HOAT - O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate;

NEW - 1-hydroxybenzotriazole;

HPLC - high performance liquid chromatography;

ίρ - intraperitoneal injection;

ίν - injection into the tail vein;

ΜΒΗΑ - 4-methylbenzhydrylamine;

ΜιηΙ - 4-methoxytrityl;

ΝΜΡ - ^ methyl-2-pyrrolidinone;

Pb £ - 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl;

sruk / 3 - three doses, one dose once a week;

8c (OH) ₃ - scandium (III) trifluoromethanesulfonate;

1 Vi - tert-butyl;

ΤΕΑ - triethylamine;

ΤΟΌ - tumor growth retardation;

ΤΟI - inhibition of tumor growth;

TT5 — triisopropylsilane;

TO8 - tosil;

Tg1 is trityl;

ΤΡΑ - trifluoroacetic acid;

TRRN - tetramethyl fluoroforamidinium hexafluorophosphate;

Ργδ-ψ (СΗ ₂ -NΗ) Τу ^ has the structure

The Greek letter ψ is used in the present description to indicate that the peptide bond is replaced by a pseudopeptide bond. When designating the amino acid sequence, the term ψ is used in the format -A-ψ (HATB, where A is an aminoacyl radical whose carbonyl group is modified to X, and B is an aminoacyl radical whose α-amino group has been modified to X '. X and X 'are shown in the form of a string of symbols of structural elements separated by a bond, for example, Ργ5-ψ (СΗ ₂ -NΗ) -Τу ^.

The specified amino acid in the designation gu (amino acid) is attached to the compound in reverse orientation. The specified amino acid in the designation gu (amino acid) can have either a b- or Ό-configuration. For example, the camptothecin-guA5p-8is molecule has the structure:

The designations ΓνΌ / b-amino acid or gu (O- / b-amino acid) refer to a mixture of b- and b-12 020613 configurations of the indicated amino acid. For example, the compound camptothecin-guP / ba8p-8is contains a mixture

AND

The term alkyl refers to a hydrocarbon group containing one or more carbon atoms, in which the carbon atoms, if several, are connected by simple bonds, examples include, but are not limited to, methyl, ethyl, propyl and butyl. The alkyl hydrocarbon group may be a straight chain or contain one or more branches or cyclic groups, examples of which include, but are not limited to, isopropyl and tert-butyl.

The term substituted alkyl refers to alkyl in which one or more hydrogen atoms of a hydrocarbon group are substituted with one or more substituents selected from the group consisting of halogen (i.e. fluorine, chlorine, bromine and iodine), OH, ΟΝ, 8H, ΝΗ ₂ , ΝΗΟΗ ₃ , ΝΟ ₂ , (C _{! -2} ) alkyl substituted with 1-6 halogen atoms, CP ₃ , OCH ₃ , OCP ₃ and (CH ₂ ) _0-4 -COOH. In various embodiments, 1, 2, 3, or 4 substituents are present. The presence of (CH ₂ ) _0-4 -COOH results in an alkyl-containing acid. Examples of alkyl acids containing (CH ₂ ) _0-4 —COOH include 2-norbornane acetic acid, tert-butyric acid, and 3-cyclopentyl propionic acid.

The term heteroalkyl refers to alkyl in which one or more carbon atoms in a hydrocarbon group are substituted by one or more of the following atoms or groups: amino, amido, O, δ, N and carbonyl. In various embodiments, 1 or 2 heteroatoms are present.

The term substituted heteroalkyl refers to heteroalkyl in which one or more carbon atoms of a hydrocarbon group are substituted by one or more substituents selected from the group consisting of halogen (i.e., fluorine, chlorine, bromine and iodine), OH, ΟΝ, 8H, ΝΠ ₂ , ΝΠΟΠ ₃ , NΟ ₂ , (C _1-2 ) alkyl substituted with 1-6 halogen atoms, CP ₃ , OCH ₃ , OCP ₃ and (CH ₂ ) _0-4 -COOH. In various embodiments, 1, 2, 3, or 4 substituents are present.

The term alkenyl refers to a hydrocarbon group formed by two or more carbon atoms in which one or more carbon-carbon double bonds are present, examples of which include, but are not limited to, vinyl, allyl, butenyl, and propenyl. An alkenyl hydrocarbon group may be a straight chain or contain one or more branches or cyclic groups, examples of which include, but are not limited to, n-butenyl relative to t-butenyl and n-pentenyl compared to cyclopentenyl.

The term substituted alkenyl refers to alkenyl in which one or more hydrogen atoms is substituted by one or more substituents selected from the group consisting of halogen (i.e., fluorine, chlorine, bromine and iodine), OH, ΟΝ, 8H, ΝΠ ₂ , Ν ^ Ή ,. NΟ ₂ , (C _1-2 ) alkyl substituted with 1-6 halogen atoms, CP ₃ , OCH ₃ , OCP ₃ and (CH ₂ ) _0-4 —COOH. In various embodiments, 1, 2, 3, or 4 substituents are present.

The term aryl refers to an optionally substituted aromatic group with at least one ring having a conjugated π-electronic system containing up to two conjugated or fused ring systems. Aryl includes, but is not limited to, a carbocyclic aryl, heterocyclic aryl and biaryl groups. Preferably, aryl is a 5- or 6-membered ring. Preferred atoms for heterocyclic aryl include, but are not limited to, one or more of sulfur, oxygen, and nitrogen atoms. Examples of aryl include, but are not limited to, phenyl, 1-naphthyl, 2-naphthyl, indole, quinoline, 2-imidazole and 9-anthracene. Aryl substituents are selected from the group consisting of (ScDalkyl, (Sc ₄ ) alkoxy, halogen (i.e. fluorine, chlorine, bromine and iodine), OH, ΟΝ, 8H, ΝΠ ₂ , NΟ ₂ , (C1 _-2 ) alkyl substituted with 1-5 halogen atoms, CP ₃ , OCP ₃ and (CH ₂ ) _0-4 —COOH. In various embodiments, aryl contains 0, 1, 2, 3 or 4 substituents.

The term alkylaryl refers to alkyl bonded to aryl as described above.

The term cycloalkyl is intended to include a monocycloalkyl or bicycloalkyl group with the indicated number of carbon atoms known to those skilled in the art.

The term heterocycle includes monocyclic and bicyclic systems with one or more heteroatoms, such as oxygen, nitrogen and sulfur. The ring system may be aromatic, for example pyridine, indole, quinoline, pyrimidine, thiophene (also known as thienyl), furan, benzothiophene, tetrazole, dihydroindole, indazole, Ν-formylindole, benzimidazole, thiazole and thiadiazole. Ring systems may also be non-aromatic, such as, but not limited to, pyrrolidine, piperidine, morpholine, and the like.

Synthesis.

The compounds of this invention can be prepared using the procedures described in the examples of this document, as well as using methods well known in the art. For example, the polypeptide region of analog ΝΡΥ can be synthesized and / or modified chemically or biochemically. Examples of biochemical synthesis techniques, including introducing nucleic acid into a cell and expressing nucleic acids, can be found, for example, in 81e ^ ay, 1.M., s1 a1., 8oPb Rkake 8up1He515. Р1егсе Сёш1са1 Со., 2 ' ¹ еб. (1984), and, for example, in Protractor (a1., Mo1ci1ag C1oppd: A baoba (ogu Mapia1, 2 ^pb Ebbyup, Co1b 8rgd Nagbbbbpg Prge88 (1989). The following examples also illustrate the methods for the synthesis of targeted cytotoxic compounds of the present invention. shown for illustrative purposes and in no way imply a limitation on the scope of the invention.

Example 1. [Ak ¹⁰ , 4 ^ ρ ³⁴ ] ΕΝΡΥ (1-36) -ΝΗ ₂ (8ЕО ΙΌ ΝΟ: 3).

The title peptide was synthesized using Rhos chemistry. The C-terminal part of the peptide (residues 18-36) was synthesized on a ΑΒΙ 433A peptide synthesizer (Arrieb Vu8u8 (et8, Po8 (ex SBU, CA, I8A)) on a synthesis scale of 1.0 mmol. 1.37 g of the Kg-amide MVNA resin with a substitution of 0.73 mmol, Schowbusbet, § Ap P1edo, CA, I8A) was placed in a reaction vessel, the resin was treated with 10 ml of ΝΜΡ for 15 min to swell the resin.

Each cycle consisted of the removal of the кон-terminal Ptos group with 20% piperidine, followed by repeated washing with PMR. The finished cartridges for each amino acid (1 mmol) were then dissolved in 0.45 M HOBT / HBT. After a time sufficient to dissolve the amino acid, it was automatically transferred to the activation vessel. Two more amino acid cartridges (1 mmol) were dissolved and transferred into a vessel for activation to a total of 3 equiv. amino acids used in the addition step. Then, ΌΙΡΕΛ (3 ml of a 2 M solution) was added to the reaction vessel to a total of 6 eq. O1REA.

All this mixture was then added to the resin and allowed to mix for 15 minutes. The reaction vessel was then released, washed with PMR, and then a second addition step was carried out. After the second addition step, the resin was again thoroughly washed. Each amino acid was attached twice in the same way. After the addition of the first residue Tug, for each of the next 4 stages of addition and each stage of addition, the Agd resin is blocked with 5 ml of blocking solution (0.5 M acetic anhydride / 0.13 M P1REA / 0.01 M HOBT) to block any un-acylated areas of the resin .

The following amino acid cartridges were used for the coupling steps:

cycle 1) Rtos-Tug ((Vi) -OH;

cycle 2) Rtos-Agd (RM) -OH;

cycle 3) Rtos-4Nur-OH;

cycle 4) Rtos-Agd (RM) -OH;

cycle 5) Ptos-Thr ((Vi) —OH;

cycle 6) Rtos-11e-OH;

cycle 7) Ptos-lei-OH;

cycle 8) Ртос-А8п (Тг () - ОН;

cycle 9) Rtos-11e-OH;

cycle 10) Rtos-Tug ((Vi) -OH;

cycle 11) Ptos-H18 (Tg () - OH;

cycle 12) Ptos-Agd (Pb) -OH;

cycle 13) Ptos-lei-OH;

cycle 14) Rtos-A1a-OH;

cycle 15) Rtos-8eg ((Vi) -OH;

cycle 16) Rtos-Tug ((Vi) -OH;

cycle 17) Rtos-Tug ((Vi) -OH;

cycle 18) Ptos-Agd (PbH) -OH and cycle 19) Ptos-A1a-OH.

After the last addition step, the resin was washed with PMR, followed by standard removal of the Ν-terminal Ptos group, washing with PMR followed by washing with OCM. After assembling the C-terminal portion of the peptide chain (residues 18-36), 0.1 gum (0.1 mmol) was used to construct the Ν-terminal portion of the peptide, and the residue was retained. The кон-terminal part of the title peptide (residues 1-17) was synthesized using PTC chemistry using microwave radiation on a Pebu peptide synthesizer (CEM, Mabbet, ΝΟ, I8A) in a synthesis scale of 0.1 mmol. The resin from the previous synthesis was placed in a 50 ml conical tube along with 15 ml of OME and loaded into the resin position on the synthesizer. The resin was then quantitatively transferred to the reaction vessel automatically. A standard Pebou synthesis protocol was used for a scale of 0.1 mmol. This

- 14 020613 protocol includes the removal of the Ν-terminal Rtos group by first treatment of 7 ml of 20% piperidine containing 0.1 M HOBT, ΌΜΕ The first deprotection was carried out for 30 s using microwaves (45 W, maximum temperature 75 ° C) and nitrogen purge (3 s purge / 7 s break). Then the reaction vessel was dried and a second piperidine treatment was carried out, similar to the first treatment, except that it lasted 3 minutes.

Then the resin was dried and washed thoroughly several times ΌΜΕ Then the protected amino acid, Ptos-Me1-OH was added as a 0.2 M concentrated solution in ΌΜΡ (2.5 ml, 5 equiv.) Followed by 1.0 ml of 0.45 M (4.5 equiv.) NVTI in ΌΜΕ After that, 0.5 ml of 2 M (10 equiv.) HEAT in ΝΜΡ was added. The addition step was carried out for 5 min using 20 W microwave radiation at a maximum temperature of 75 ° C, and with the same ratio of nitrogen purge time and break time. After the first coupling step, the contents of the reaction vessel were discarded and the coupling step was repeated.

Then, cycle 2 was started similarly to cycle 1. All amino acids were introduced in a similar manner and the double addition strategy was used for the entire sequence. Upon addition of residues 9-10 (O1y-A1b), the blocking procedure was used immediately after the addition step.

Blocking was performed by adding 7 ml of 0.5 M acetic anhydride containing 0.015 M HOBT in ΝΜΡ, together with 2 ml of 2 M solution ΌΙΡΕΑ using a multi-stage microwave processing protocol: at a power of 50 W for 30 s (maximum temperature - 65 ° C) followed by a break for 30 s and the next round of a 30-second microwave treatment (50 W), and a subsequent 30-second break. The resin was dried and washed thoroughly ΌΜΡ. The following amino acids were used (Ayuapsey SyetGesy, LoshuShe, ΚΥ, I8A):

cycle 20) Ptos-Ge-OH; cycle 21) Ртос-А8р (ОГВи) -ОН; cycle 22) Rtos-O1i (OGVi) -OH; cycle 23) Ptos-A1a-OH; cycle 24) Rtos-Rgo-OH; cycle 25) Rtos-A1a-OH; cycle 26) Rtos-A8r (OGVi) -OH; cycle 27) Ptos-AB-OH; cycle 28) Rtos-O1u-OH; cycle 29) Rtos-Rgo-OH; cycle 30) Ptos-Agp (Tg) -OH; cycle 31) Ртос-А8р (ОГВи) -ОН; cycle 32) Rtos-Rgo-OH; cycle 33) Ptos-Li8 (Boc) -OH; cycle 34) Rtos-8eg (GVi) -OH; cycle 35) Rtos-Rgo-OH; cycle 36) Rtos-Tug (GVi) -OH.

After completion of the synthesis of the peptide chain, standard piperidine treatment was used to remove the Ν-terminal Ptos group using the standard deprotection procedure described above. The resin was thoroughly washed with ΌΜΤ and then placed back into a 50 ml conical tube, using ΌΜΤ as a solvent for transfer.

The peptide was deprotected and cleaved from the resin by treatment with 5 ml of the following reagent: 5% ΤΙ8, 2% water, 5% (w / v) OTT and 88% TPA and stirring for 3.5 hours. The filtrate was collected in 45 ml of cold anhydrous ethyl ether. The precipitate was besieged for 10 min at 3500 rpm in a cooled centrifuge. The ether was decanted and the peptide was dissolved in fresh ether. Treatment with ethyl ether was carried out only 2 times. After the last washing with ether, the peptide was allowed to air dry to remove ether residues. The peptide precipitate was resuspended in 8 ml of acetonitrile, followed by the addition of 8 ml of deionized water and allowed to dissolve completely.

The peptide solution was then analyzed by mass spectrometry. Mass spectrometric analysis using ionization by atomization in an electric field identified the main product with a mass of 4212.1, corresponding to the target product. Analysis by analytical HPLC on a C18 column of 250x4.6 mm (Ryepotepech, Toggaps, CA, I8A) in a gradient of acetonitrile of 2-60% (0.1% TPA) for 30 min identified the main product with a purity of 45%. The crude peptide was then purified by preparative HPLC on a C18 reverse phase column in a gradient of acetonitrile of 10-60% (0.1% TPA) for 50 min at a flow rate of 10 ml / min. The purified product was analyzed by HPLC for purity (> 99%) and by mass spectrometry to determine the mass (4212.8 Da), and the experimentally determined mass was in good agreement with the expected mass of 4212.7. Then the peptide was lyophilized to obtain 39 mg of purified product in 9% yield.

- 15,020,613

Example 91. [Camptothecin-guO1u-§is-Tug ¹ , 1. CPT-guO1u-Vos

Me ¹⁷ , Ργο ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ ₂ (Zeo ΙΌ N0: 88).

Camptothecin (CPT) (6.0 g, 17.2 mmol), Boc-O1y-OH (10.0 g, 57.0 mmol), ΌΜΆΡ (6.4 g, 52.2 mmol), 8 s (0 ( D) ₃ (5.0 g, 10.2 mmol) and ΌΙΕΆ (6.0 ml, 34.4 mmol) were added to a 500 ml round bottom flask containing an ESM / EMR (300/30 ml). EES (13.0 g, 68.0 mmol) was added in one portion over 10 minutes, the reaction mixture was stirred at room temperature for 16 hours, it gradually changed from suspension to a clear solution, the OSM was removed on a rotary evaporator, and the remaining solution was transferred into в into MeOH (200 ml) and placed in a refrigerator. Yellow crystals (formed in 2 -16 h) was filtered off and washed with hexane.The solid was obtained after drying in air (5.9 g).

TPA (70 ml) was added to a solution of CPT-guO1y-Boc (3.3 g, 6.5 mmol) in OSM (70 ml). The reaction mixture was stirred at room temperature for 2 hours. Then ether (450 ml) was added and a yellow solid was obtained after filtration, followed by washing with ether (3.1 g).

3. SRT-guO1u-8is-OH

The compound C. Р PT-gCiu Н H ₂ (6.5 mmol) obtained above was dissolved in EMR (90 ml). Succinic anhydride (1.2 g, 11.9 mmol) and TEM (3.2 ml, 22.7 mmol) were added. The mixture was stirred at room temperature for 4 hours. Then the mixture was poured into a glass of ice water (1200 ml) and treated with concentrated HCl to pH ~ 3. The yellow solid was filtered off and washed with water. A solid was obtained after drying under high vacuum (3.77 g).

4. Protected peptide [Tug ¹ , Me ¹⁷ , P ^ o ³⁴ ] LNPΥ (1-36) -Κ ^ ηk-amide MVNA resin (ZEO GO N0: 88)

were obtained on a peptide synthesizer AB1 433a in a scale of 0.25 mmol using a Ktik-amide MVNA resin (load 0.69 mmol / g, 0.365 g) and RTOS chemistry with two prolonged stages of attachment, as well as with the final removal of protection to remove Rthos groups with Tug ¹ . After completion of the synthesis, the protected peptide on the resin was dried in air, whereby a solid (0.455 g) was obtained.

- 16,020,613

5. [Kamptothecin-guO1u-8is-Tug ¹ , Me '. Ρ ^ о ³⁴ ] LNΡΥ (1-36) NН ₂ (8ЕО ΙΌ НО: 88)

СΡТ- ^ νΟ1у-8is-OH (190 mg, 0.38 mmol), NEW! (85 mg, 0.63 mmol), E1C (0.098 ml, 0.63 mmol) and O1EA (1.2 ml, 6.9 mmol). After shaking for 16 hours, the mixture was dried and washed 3 times ΌΜΡ and then 3 times with ESM. The resin was then treated with a mixture of TPA: T18: water (9.5: 0.8: 0.85 ml) for 3 hours. After filtration, ether (80 ml) was added to the filtrate to remove the resin. A yellow precipitate was collected by centrifugation. The crude product was redissolved in a mixture of 10 ml of water with 5 ml of acetonitrile and purified by preparative HPLC (column C18). Fractions containing the desired product (confirmed by mass spectrometry and HPLC) were combined and lyophilized. A yellow solid (28.4 mg) was obtained. Mass spectrometric analysis with ionization in an electric field showed a molecular weight of 4709.9 (which is consistent with the calculated molecular weight of 4709.9). Purity by HPLC analysis was 97.5%.

Example 92 / 92A: [Camptothecin-guP / La5p-8is-Tug ¹ , Me ', 4 ^ ρ ³⁴ ] ΗΝΡΥ (1-36) ΝΉ ₂ (8ЕО ΙΌ ИО: 89)

1. СΡТ- ^ ν ^ / ^ а8ρ (ОίВи) -Вос

СΡТ (1.5 g, 4.3 mol), Boc-Agr (О1Ви) -ОН (4.1 g, 14.2 mmol), ΌΜΆΡ (1.6 g, 13.1 mmol), 8 s ( OH) ₃ (1.25 g, 2.5 mmol) and O1EA (1.5 ml, 8.6 mmol) were added to a 250 ml round bottom flask containing OSM / ΌΜΡ (75/20 ml). After stirring for 10 minutes, EOS (3.25 g, 17.0 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 2-16 hours. It gradually changed from suspension to a clear solution. The ESM was removed on a rotary evaporator and the remaining solution ΌΜΡ was treated with ice water. After filtration and drying under high vacuum, a yellow solid (3.4 g) was obtained. HPLC analysis revealed two peaks indicating the presence of two S and B isomers in a 4: 1 ratio.

To a suspension of crude С раствораТ- ^ ν ^ / ^ а8ρ (ОВВи) -Вос (1.1 g, 1.7 mmol) in 1-ViOH (50 ml) was added 50 ml of a 4 M solution of HCl in dioxane. The reaction mixture was stirred at room temperature for 25 minutes. Then ether (900 ml) was added and a fine yellow precipitate was obtained.

The above obtained СΡТ- ^ ν ^ / ^ а8ρ (ОВВи) -НН ₂ (1.7 mmol) was dissolved in 20 ml of ΌΜΡ. Succinic anhydride (0.28 g, 2.8 mmol) and TEM (0.8 ml, 5.7 mmol) were added. The mixture was stirred at room temperature for 16 hours. Then the mixture was poured into a glass of ice water (200 ml) and treated with concentrated HCl to pH ~ 3. A finely divided yellow solid (0.72 g) was obtained. HPLC analysis revealed two peaks in a 4: 1 ratio.

4. Protected peptide [Tug ¹ , Ν1β ¹⁷ , 4Nur ³ ' ¹ | kNRU (1-36) -K | pc-amide MVNA-resin (Betz ΙΌ ΝΟ: 89).

The specified peptide was obtained using a procedure similar to the procedure in example 81.

5. [Kamptothecin-guP / Lacr-Bis-Tug ¹ , Ν1β ¹⁷ , 4Nur ³⁴ ] KYRU (1-36) MN ₂ (Betz GO ΝΟ: 89).

To the mixture of the protected peptide [Tug ¹ , Ν1β ¹⁷ , 4 Nur ³⁴ ] KCHR (1-36) -Kshk-amide MVNA-resin (0.125 mmol) and ΌΜΡ (5 ml) was added CPT- ^ y ^ / ^ a8p (ΟίBi) - Bis-ΟΗ (230 mg, 0.37 mmol), ΗΟΒΐ (84 mg, 0.63 mmol), EH (0.097 ml, 0.63 mmol) and EGOA (1.3 ml, 7.5 mmol). The procedure was followed similar to that of Example 81. The amount of purified material obtained was 31.0 mg. The molecular weight calculated using mass spectrometric analysis with ionization in an electric field was 4783.8 (which is consistent with the calculated molecular weight of 4784.2). Purity by analytical HPLC was 100%.

Example 93. [Camptothecin-tuP / L-Akr-Bis-Tug ¹ , Ν1β ¹⁷ , A6c ³¹ , 4 Nur ³⁴ ] KCHRU (1-36) -CHN ₂ (Betz GO ΝΟ: 90).

[CPT- ^ y ^ / ^ a8p-Bis-Tu ^ ¹ , Ν1β ¹⁷ , A6c ³¹ , 4Nur ³⁴ ] kYRU (1-36) -CHN _{2 was} obtained analogously to example 82 from CPT-^ y ^ / ^ a8p (ΟίВи) -Bis-ΟΗ and the corresponding peptide [Tug ¹ , Ν1β ¹⁷ , A6c ³¹ , 4Nur ³ ' ¹ | kNRU (1-36) -K | pycamide MVNA-resin. The amount of purified material obtained was 23.0 mg. Mass spectrometric analysis with ionization in an electric field showed that the molecular weight was 4796.0 (which is consistent with the calculated molecular weight of 4796.2). Purity by analytical HPLC was 100%.

Other compounds of the invention can be obtained by one of ordinary skill in the art using synthesis procedures similar to those described in the above examples. The physical parameters of the compounds of examples 1-77 and 91-107 are given in table. one.

- 18,020,613

Table 1

Example Number Like weight (expected) Like weight (according to Ε5Ι-Μ5) % purity (HPLC) one 4212.7 4212.8 99.9 2 4210.6 4210.6 99.9 3 4180.6 4180.5 99.9 4 4236.7 4257.3 98.2 5 4254.7 4255.0 98.7 6 4268.7 4268.9 98.8 7 4268.7 4268.7 97.3 8 4268.7 4268.9 96.7 nine 4254.7 4254.8 96.3

10 4268.7 4268.9 95.6 eleven 4226.7 4227.0 95.2 12 4270.7 4270.9 99.9 thirteen 4227.7 4227.4 99.9 14 4240.7 4241.0 99.9 fifteen 4270.7 4270.6 99.9 sixteen 4250.7 4250.9 99.9 17 4226.7 4226.9 99.9 eighteen 4270.7 4270.8 99.9 nineteen 4270.7 4270.5 99.9 twenty 4212.7 4212.7 99.9 21 4226.7 4226.8 99.9 22 4227.7 4227.8 99.9 23 4284.8 4284.7 99.9 24 4166.6 4166.9 99.9 25 4166.6 4166.6 99.9 26 4164.7 4164.7 98.1 27 4150.7 4150.4 99.9 28 4136.6 4136.5 99.9 29th 4180.6 4181.0 99.9 thirty 4122.6 4122.6 99.9 31 4196.7 4197.0 98.9 32 4182.7 4182.7 99.9 33 4180.7 4180.9 99.9 34 4180.6 4180.5 99.9 35 4206.6 4206.8 99.9 36 4216.6 4217.0 99.9 37 4230.6 4231.1 99.9 38 4168.6 4168.2 99.9 39 4138.6 4139.1 99.9 . 40 4416.1 4415.9 > 99 41 4423.1 4423.4 > 99 42 4466.1 4466.1 > 98

- 19,020,613

43 4508.2 4508.2 > 98 44 4492.2 4491.9 > 99 45 4416.1 4416.4 > 99 46 4416.1 4416.5 > 99 47 4423.1 4423.2 > 97 48 4508.2 4508.4 > 99 49 4448.0 4448.2 > 99 fifty 4464.2 4463.7 > 99 51 4450.1 4450.5 > 99 52 4508.2 4508.3 > 99 53 4508.2 4508.4 > 99 54 4464.2 4464.9 > 99 55 4450.1 4450.3 > 99 56 4522.2 4522.2 > 99 57 4465.1 4465.1 > 99

58 4464.2 4464.2 > 99 59 4451.1 4451.2 > 99 60 4492.2 4492.0 > 99 61 4416.1 4416.3 > 99 62 4579.2 4579.2 > 99 63 4423.1 4422.8 > 99 64 4478.1 4478.1 > 99 65 4466.1 4466.3 > 99 66 4466.1 4466.3 > 99 67 4465.1 4465.2 > 99 68 4466.1 4466.1 > 99 69 4416.1 4416.4 > 99 70 4442.1 4442.4 > 99 71 4423.1 4423.2 > 99 72 4254.7 4255.4 97.7 73 4254.7 4255.9 98.2 74 4238.7 4238.5 99.9 75 4254.7 4254.7 96.5 76 4302.8 4302.7 98.8 77 4482.1 4482.4 > 99 90A 4376.9 4377.4 95.2 91 4710.1 4709.9 97.5 92 / 92A 4784.2 4783.8 one hundred 93 / 93A 4796.2 4796.0 one hundred 94 4738.1 4738.2 one hundred 95 / 95A 4768.2 4767.9 one hundred 96 / 96A 4806.3 4806.2 one hundred 97 4726.1 4726.1 98.6 98 5161.6 5161.7 one hundred 99 5330.8 5330.7 99.9 100 / 100A 5219.6 5220.2 99.9 101 5330.8 5331.0 99.9 102 / 102A 5388.9 5389.3 99.9 103 / SWA 5388.9 5389.8 99.9 104 4694.1 4694.8 99.9 105 4537.9 4538.2 99.9 106 5129.6 5129.3 99.9 107 5298.8 5298.9 99.9

Ιη νίίτο radioligand analysis of binding of the ΝΡΥ-Υ1 and ΝΡΥ-Υ2 receptor.

Human neuroblastoma cell lines, δΚ-Ν-MS and ZK ^ -BE2 (American Type Culture Collection, Kosk \ 'P1e. MO, IZA) expressing the ΝΡΥ-Υ1 and ΝΡΥ-Υ2 receptors, respectively, were cultured in 10% EMEM medium fetal bovine serum and 5% chicken embryo extract, at 37 ° C in a humid atmosphere in 95% air and 5% CO ₂ .

For the radioligand analysis of the binding of ίίη νίίτο ΝΡΥ-Υ1 and ΝΡΥ-соответствующие2, the corresponding cells (ΞΚ-для-MS for ΝΡΥ-Υ1; ZK- ^ BE2 for ΝΡΥ-Υ2) were collected and homogenized in 20 ml of ice-cold 50 mM TG18-HC1 using a Vppt Po1u1gop (No. e81bigu, ΝΥ, ISA) (on parameter 6, 15 s). The homogenates were washed twice by centrifugation (39000 / d for 10 min) and the final pellets were resuspended in 50 mM TG15-HC1 containing 2.5 mM Μ βΟ ₂ . 0.1 mg / ml bacitracin (§1§ Skepisac δΐ. Losh5, ΜΟ, υδΑ) and 0.1% ΒδΑ.

For analysis, aliquots (0.4 ml) of the prepared suspensions were incubated with 0.05 nM [ ¹²⁵ Γ | ΡΥΥ (2200 Ci / mmol, Regk | p-H1teg, Βθ5ΐοη, ΜΑ) in the presence or absence of 0.05 ml of unlabeled competitive test peptide or test directed cytotoxic compounds. After a 100-minute incubation (at 25 ° C), the bound [ ¹²⁵ Γ | ΡΥΎ was separated from the free one by rapid filtration through OP / C filters (Lapbek Oakkege Ligd, ΜΌ, υδΑ), which were previously soaked in a 0.3% solution of polyethyleneimine . The filters were then washed three times with 5 ml aliquots of ice-cold 50 mM TP5-HC1 and the bound radioactivity retained on the filters was measured using gamma spectrometry (\ ν; · ι11; κ bKB, Oakkege Ligd, ΜΌ, υδΑ).

Specific binding was defined as the total amount of bound [ ¹²⁵ Γ | ΡΥΎ minus the amount bound in the presence of 1000 nM ΡΥΥ ascetic, Toggeps, СΑ, υδΑ). Inhibition constants (Κί) were calculated using the well-known Cheng-Prusov equation, and these data, together with the selectivity of these compounds with respect to ΝΡΥ-Υ1 and ΝΡΥ-Υ2, are given in table. 2.

Each of the compounds from examples 1-38, 40-61, 64-77 and 91-103 was tested in the above radioligand analyzes, and it was found that almost all of these compounds had Κί below 100 nM, as well as some of the compounds from examples had Κί in the subnanomolar range. It was also found that almost all of these compounds highly selectively bound ΝΡΥ-Υ1 compared to ΝΡΥ-Υ2.

table 2

Example Number K1 (nM) davU1 Κι <ηΜ) μιΥ2 Beat up one 0.04 198 Υ1 2 0.08 > 1000 Υ1 3 0.11 944 Υ1 4 0.21 658 Υ1 5 0.68 420 Υ1 b 0.31 319 Υ1 7 0.60 347 Υ1 8 3.48 52 Υ1 nine 2.58 420 Υ1

10 0.98 578 Υ1 eleven 2.95 178 Υ1 12 1.19 505 Υ1 thirteen 3.47 727 Υ1 14 257.27 > 1000 Υ1 fifteen 0.26 710 Υ1 sixteen 0.29 > 1000 Υ1 17 0.03 595 Υ1 eighteen 0.21 171 Υ1 nineteen 0.24 997 Υ1 twenty 0.20 > 1000 Υ1 21 0.13 45 Υ1 22 1.23 > 1000 Υ1 23 0.20 > 1000 Υ1 24 0.19 > 1000 Υ1

- 21,020,613

25 0.85 841 Υ1 26 0.94 198 Υ1 27 0.74 104 Υ1 28 0.18 441 Υ1 29th 1.16 > 1000 Υ1 thirty 0.59 766 Υ1 31 1.91 202 Υ1 32 1.40 483 Υ1 33 239.06 > 1000 Υ1 34 69.78 > 1000 Υ1 35 3.58 > 1000 Υ1 36 34.23 > 1000 Υ1 37 52.94 > 1000 Υ1 38 502.28 > 1000 Υ1 39 There is no data There is no data There is no data 40 307.67 367 Υ1 41 120.44 643 Υ1 42 3.56 668 Υ1 43 19.67 > 1000 Υ1 44 4.79 133 Υ1 45 10.65 nineteen Υ1 46 108.38 thirteen Υ2 47 13.66 fifteen Υ1 48 6.68 10 ΥΙ 49 54.26 eleven Υ2 fifty 20.35 26 Υ1 51 10.00 611 Υ1 52 6.18 383 Υ1 53 22.50 270 Υ1 54 4.79 40 ΥΙ 55 5.68 23 Υ1 56 11.82 41 Υ1 57 2.94 74 Υ1

58 3.44 33 Υ1 59 1.49 75 Υ1 60 0.55 138 Υ1 61 0.73 80 ΥΙ 62 There is no data There is no data There is no data 63 There is no data There is no data There is no data 64 87.47 227 Υ1 65 35.17 > 1000 ΥΙ bb 10.35 292 Υ1 67 29.67 267 Υ1 68 53.58 > 1000 Υ1 69 187.50 787 Υ1 70 8.24 107 Υ1 71 21.57 > 1000 Υ1 72 11.80 895 Υ1 73 9.68 > 1000 Υ1

- 22,020,613

74 0.48 466 Υ1 75 0.67 22 Υ1 76 1.44 151 Υ1 77 55.85 38 Υ2 90A 0.84 672 Υ1 91 0.79 > 1000 Υ1 92 / 92A 0.63 > 1000 Υ1 93 / 93A 4.10 > 1000 Υ1 94 1.60 407 Υ1 95 / 95A 3.96 256 Υ1 96 / 96A 06/23 623 Υ1 97 1.98 699 Υ1 98 2.08 There is no data There is no data 99 7.55 There is no data There is no data 100 / 100A 7.70 There is no data There is no data 101 2.92 There is no data There is no data 102 / 102A 7.59 There is no data There is no data 103 / SWA 7.74 There is no data There is no data

Tumor growth analysis ίη νίνο.

The compounds of Examples 91, 92, and 93 were evaluated in two studies: Study A and Study B, each of which used one group (η = 10) of non-exposed animals, one group of carrier-treated animals and one group of animals treated with unconjugated camptothecin b the amount of 7.5 mg / kg The introduction was carried out once a week for three weeks by injection into the tail vein, with the exception of cases where poor solubility of the drug compound or tail necrosis required intraperitoneal injection. In study A, groups of mice were evaluated that received the compound from Example 91 in an amount of 55.65, 111.3 and 222.6 mg / kg and from Example 92 in an amount of 55.3, 110.6 and 221.2 mg / kg. The compound of Example 93 was evaluated in Study B at 55.45, 110.9, and 221.8 mg / kg. Antitumor activity was evaluated by tumor growth retardation (ΤΟΌ), defined as the difference in median time to reach the final tumor size in the study group relative to the control group, and by tumor growth inhibition (ΤΟΙ), defined as the difference between median tumor volumes in the groups who received the test effect and the control group on the day of the study, which provides a balance between measurable responses in the group and large group sizes. Toxicity was evaluated by body weight and clinical observations.

On day 1 (the definition of Day 1 is given below), the age of female nude mice (pi / pi, Nag1ap) was 10-11 weeks, and their weight was in the range of 20.2-31.1 g and 21.2-29.8 g The animals received Ay HbPit water (purified by reverse osmosis, containing 1 ppm С1) and radiation sterilized using radiation No. H 31 MoiShay apy 1gay1a1ey Lab ΟίοΙ®, consisting of 18% crude protein, 5% crude fat and 5% crude fiber . The mice were kept on a radiation-sterilized litter for laboratory animals ALRNL-ip® Ley-o'coB8® in fixed micro-insulators on a 12-hour light cycle at 21-22 ° C (70-72 ° P) and 40-60% humidity.

MCP-7 human mammary carcinoma cells were grown in medium ΜΙ3ΜΙ1640 containing 100 u / ml of penicillin O sodium, 100 μg / ml of streptomycin sulfate and 25 μg / ml of gentamicin. On Wednesday, 10% heat-inactivated fetal bovine serum and 2 mM glutamine were added. Additional buffer capacity was provided with 10 mM HEPE8 and 0.075% sodium bicarbonate. Tumor cells were cultured in tissue culture vials in a humidified incubator at 37 ° C in an atmosphere consisting of 95% air and 5% CO ₂ .

3-7 days before the injection of the cells of each mouse, a capsule containing 17-β-estradiol was implanted between the shoulder blades (0.36 mg, release over 60 days, Iηηονаΐ ^ νе Kekeages οί Ateps).

MCP-7 tumor cells used for implantation were collected during the logarithmic growth phase and resuspended in phosphate-buffered saline in an amount of 5x10 ⁷ cells / ml. Each mouse was injected subcutaneously by injection into the right flank of 1x10 ⁷ cells. The development of tumors was observed twice a week and then daily after the tumor reaches a volume of 80-120 mm ³ . On day 18, which was designated Day 1 in study A, animals were sorted into nine groups (number of animals in the group, n = 10) with individual tumor sizes ranging from 63 to 172 mm ³ and average tumor volume in the group constituting 123.7-124.6 mm ³ . Due to poor tumor survival, the number of animals was insufficient for the additional three groups included in the original protocol. Therefore, a separate study was conducted (Study B), which included six groups (n = 10) of animals. In this study, 17 days elapsed between cell implantation and group separation. Individual tumor sizes on day 1 ranged from 63 to 221 mm ³ , and the average tumor volume for the groups ranged from 112.7 to 113.6 mm ³ . Tumor size in mm ^{3 was} calculated by the formula

- 23,020,613

in which № = width, and 1 = length in mm of the MCP-7 tumor.

Tumor weight was estimated on the assumption that 1 mg is 1 mm ³ of tumor volume.

Dosages of the compounds of Examples 91 and 92 were prepared in a 5% dextrose in water (E5A) solution on day 1. Due to poor solubility, dosages of these agents on days 8 and 15 were prepared in 0.1N. acetic acid.

Dosages for the compound of Example 93 were prepared fresh in 0.1N. acetic acid for each day the mice received exposure. To increase solubility, the most concentrated solution of the substance from Example 83 (221.8 mg / kg) was prepared in half concentration, sonicated in a water bath at 60 ° C and injected with a double volume (0.4 ml per 20 g of mouse) relative to the protocol .

Concentrated camptothecin solutions (batch No. 034K3648, 81dsha) were prepared in 60% OMA and 40% T \ uep 80 and stored at room temperature for the duration of the study. Dosages were prepared fresh for each day of administration by diluting concentrated 1:20 solutions in physiological saline.

The general exposure scheme is given in table. 3A for study A and table. 3B for study B.

Table 3A

Group η Exposure pattern Agent mg / kg Way introductions Scheme introductions one 10 Not impacts 2 10 Carrier* - IV SGDKhZ 3 10 Example 91 55.65 XV srlgkhz 4 10 Example 91 111.3 XV f \ gkhkhz 5 10 Example 91 222.6 XV Wed / khZ 6 10 Camptothecin 7.5 XV srtkhz 7 10 Example 92 55.3 XV <ZugkhZ 8 10 Example 92 110.6 XV dmkhz nine 10 Example 92 221.2 XV DGKHZ

* Carrier = 0.1n. acetic acid.

- 24,020,613

Table 3B

Group η Exposure pattern Agent mg / kg Way introductions Scheme introductions one 10 Not impacts 2 10 Carrier** - ίρ IDI XV Wed / khZ 3 10 Camptothecin 7.5 XV arc3 4 10 Example 93 55.45 IV dmkhz 5 10 Example 93 110.9 ίν srtkhz 6 10 Example 93 221.8 ίν dmkhz

** Mice from group 2 received a carrier of 3% OAA. 2% Tosheep 80, 1) 5 \ U. ιρ, on day 1 and the carrier 0.1N. acetic acid on days 8 and 15.

All influences and carriers were administered in an amount of three doses, once a week (with | \\ x3). Mice from the 1st group did not receive food through a probe and did not receive injections, and they served as a control of tumor development and estrogen toxicity. Animals from the 2nd group received a carrier.

In study A (Table 3A), mice in groups 3, 4, and 5 received the compound from Example 91 in the amount of 55.65, 111.3, and 222.6 mg / kg, respectively, by intraperitoneal injection (ιρ) on day 1 and by injection into the tail vein (ίν) on days 8 and 15. Camptothecin in an amount of 7.5 mg / kg was administered to mice in group 6, ίρ on day 1 and ίν on days 8 and 15. To mice in groups 7, 8 and 9 were administered the compound from example 92 in the amount of 55.3, 110.6 and 221.2 mg / kg respectively ίρ on day 1 and иν on days 8 and 15.

In study B (Table 3B), animals in group 3 received camptothecin 7.5 mg / kg ίν on days 1 and 8 and ίρ on day 15. Mice from groups 4, 5, and 6 were administered the compound of Example 93 in an amount of 55.45 , 110.9 and 221.8 mg / kg ίν on days 1 and 8 and ίρ on day 15.

Each dose was administered in a volume of 0.2 ml per 20 g of body weight and scaled depending on the body weight of the animal.

Curves of the median tumor growth in FIG. 1-3 show the median tumor volume as a function of time. If the animal was withdrawn from the experiment as a result of the size of the tumor, then the final tumor volume recorded for the animal was included along with the data used to calculate the median tumor volume for the group at subsequent time points. The curves ended after 50% of the animals in the group were withdrawn from the experiment.

In FIG. Figure 1 shows the curves of the median tumor growth for the compound of Example 91, which show the w νί \ Ό effects of the compound of Example 91 in three different dosages on the median tumor growth in Study A compared to the absence of treatment and treatment with camptothecin alone.

In FIG. Figure 2 shows the curves of the median tumor growth for the compound of Example 92, which show the w νί \ Ό effects of the compound of Example 92 in three different dosages on the median tumor growth in Study A compared to the absence of treatment and treatment with camptothecin alone.

In FIG. Figure 3 shows the curves of the median tumor growth for the compound of Example 93, which show the w νί \ Ό effects of the compound of Example 93 in three different dosages on the median tumor growth compared to the absence of treatment and treatment with camptothecin alone.

The source data from study A are given in table. 4A, in which columns Ό1-Ό39 refer to days 1-39 described above, and lines 01-09 refer to groups 1-9 described in table. 3A, and in which the average tumor volume (mm ³ ) was recorded in accordance with the day and group indicated in the table. 4A.

Table 4A

O1 ϋ4 d7 About 11 Ts 14 ϋ 18 ϋ21 ϋ25 E28 ϋ32 Ο 35 Π 39 01 123.7 139.3 161 234.2 282 378 460.6 600.4 617.7 715.9 863.8 η / ο 02 124.6 141.6 176.8 236.7 292.7 380.8 415.4 472.7 467 580.5 673.8 728.1 03 124.1 130.4 166.7 205.8 264.1 326.8 347.8 449.1 545.7 555.3 521.6 473.3 04 124.1 125.4 133.8 142.2 196 208.3 222.3 349.1 414.4 505.9 610.0 813 05 124.1 84.2 58.8 41.9 42.3 31.2 29.6 29.6 25.9 33.5 58.8 66.9 About 124.1 97.4 93.1 75 106.6 93.9 106.8 116.1 130.7 166 313.9 465 07 124.1 112.3 139.2 168.4 250.9 242.9 262.5 385.9 505.1 532.2 631 978 08 124.1 130.8 127.5 146 184.6 187.9 216.2 337.3 439.6 454.8 550.5 938 09 124.1 118.3 118.9 118.8 109.4 129.5 150.1 172.2 197.7 213.8 301.7 372

- 25,020,613

The initial data for study B are given in table. 4B, in which columns Ό1-Ό40 refer to days 1-40 described above, 01-06 refer to groups 1-6 described in table. 3B, and in which the average tumor volume (mm ³ ) was recorded in accordance with the day and the group indicated in the table. 4B.

Table 4B

ϋΐ 04 ϋ8 ϋ 12 015 ϋ 19 E22 0 26 0 29 0 33 About 36 About 40 01 113.6 262.9 261.9 304 428.5 605.1 679.9 606.8 615.7 375.8 403.2 4002 C2 112.7 274.3 269.4 329.4 453.3 562.5 550.3 637.3 393.7 479.5 626 398 Oz 112.8 169.3 171 156.7 196.7 222.3 212.3 158.9 120.2 165.6 197.4 298.6 04 112.9 206.3 227.6 236.1 323.1 348.4 343.3 366.9 426.8 524.5 621.9 452.8 C5 112.8 217.3 213 186.6 242.5 212.6 207.7 225.5 308.7 112.3 141.1 229.5 06 112.7 197.9 170.3 108 122.8 66.6 66 80.4 90.1 109.6 123.8 233.2

In Study A, the conjugate from Example 91 gave a dose-dependent LLP that became statistically significant at the highest dose, 222.6 mg / kg, and 4/4 of the tumor regression in the TOE-evaluated sample. An analysis on day 18 revealed a dose-dependent antitumor activity with potential therapeutic value at the highest dosage.

In Study A, the conjugate of Example 92 gave a dose-dependent LLP that became statistically significant and yielded 3/5 of tumor regression at the highest dose, 221.2 mg / kg. TOI on day 18 was also dose-dependent, statistically significant at 110.6 and 221.2 mg / kg, and indicated potential therapeutic significance at the highest dosage.

In study B, the conjugate from Example 93 was evaluated. Tumor growth curves indicated a clear slowdown in tumor growth at all dosages, although the LLP analysis did not distinguish responses to the compound from Example 93 from tumor growth in the untreated control group. Analysis on the 15th day revealed 71 and 77% TOI at dosages of 110.9 and 221.8 mg / kg, respectively, of potential therapeutic value.

In general, the three conjugates evaluated in studies A and B showed potential therapeutic effects for the MCP-7 xenograft in athymic mice. In particular, at the maximum studied dosages, the activity of conjugates exceeded the activity of unconjugated camptothecin in an amount of 7.5 mg / kg.

PK analysis.

The pK profile for a subgroup of compounds was determined using standard laboratory mice and standard laboratory procedures. One of skill in the art will recognize and understand that many mammals, including mice, rats, and monkeys, and modifications to this method, such as dose changes, timing, or assay modes, can also be used to make this determination.

A dose of 4 mg / kg of the compounds was administered intravenously to two mice at one time in accordance with Examples 91, 92, 93 or 96. Blood samples were taken 5, 15, 30, 60, 120, 180, 240, 360 minutes after administration.

Plasma samples (20 μl) were acidified with 2 μl of 20% acetic acid and precipitated with 60 μl of acetonitrile. The resulting solution was centrifuged. The supernatant (20 μl) was diluted in 100 μl of 0.1% aqueous acetic acid and 50 μl was injected for analysis with LBC-MB (liquid chromatography with mass spectrometric detector) in an APP4000 mass spectrometric system. Liquid chromatography conditions were as follows: buffer A was 1% formic acid in water and buffer B was 1% formic acid in acetonitrile. A gradient of 15 to 90% B for 10 min was passed at a flow rate of 0.3 ml / min using a Lump C8 (2) 2x30 mm 3i column. The elimination half-life, the area under the curve (AIS) and the excretion (Cb) are presented in table. 5.

Table 5

Example 91 Example 92 Example 93 Example 96 Τι / ₂ , hours 0.31 0, 20 Data are absent 0, 32 Ais, mcg-h / ml 1.9 3, 4 Data are absent 26.3 Cb, ml / h 2132 1166 Data are absent 150

Introduction

The peptides of this invention can be provided in the form of pharmaceutically acceptable salts. Examples of such salts include, but are not limited to, salts formed by organic acids (e.g., acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, methanesulfonic, toluenesulfonic or pamic acids), inorganic acids (for example, 26,020,613 measures, hydrochloric, sulfuric or phosphoric acids) and polymeric acids (for example, tannic acid, carboxymethyl cellulose, polylactic, polyglycolic acids or polylactic-glycolic acid copolymers). A conventional method for preparing a salt of a peptide of the present invention is well known in the art and can be performed by standard salt exchange methods. Accordingly, the trifluoroacetic acid salt of the peptide of the present invention (the TPA salt is formed by purification of the peptide using preparative HPLC with elution with buffer solutions containing TPA) can be converted into another salt, such as an acetate salt, by dissolving the peptide in a small amount of 0.25 N . aqueous solution of acetic acid. The resulting solution was applied to a semi-preparative HPLC column (2xBax, 300 BV, C-8). The column is eluted with (1) 0.1N. an aqueous solution of ammonium acetate for 0.5 h, (2) 0.25N. aqueous solution of acetic acid for 0.5 h and (3) a linear gradient (from 20 to 100% solution B in 30 min) at a flow rate of 4 ml / min (solution A is 0.25N aqueous solution of acetic acid; solution B is a 0.25N solution of acetic acid in a mixture of acetonitrile / water, 80/20). Fractions containing the peptide are collected and lyophilized.

The dosage of the active ingredient in the compositions of this invention may vary, however, it is necessary that the amount of the active ingredient be sufficient to obtain the appropriate dosage form. The specific dosage depends on the desired therapeutic effect, route of administration and duration of treatment. In general, an effective dosage for the activity of the present invention is in the range from 1x10 ^-7 to 200 mg / kg / day, preferably from 1x10 ^-4 to 100 mg / kg / day, which can be administered in a single dose or divided into several doses.

The compounds of the present invention can be administered orally, parenterally (for example, by intramuscular, intraperitoneal, intravenous or subcutaneous injection or implants), nasally, vaginally, rectally, sublingually or topically, and the compounds can be formulated together with pharmaceutically acceptable carriers to obtain dosage forms suitable for each route of administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable carrier, such as sucrose, lactose or starch. Such dosage forms also typically contain additional substances, in addition to such inert diluents, for example, lubricants, such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents. Tablets and pills can be further prepared with an enteric coating.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, containing inert diluents commonly used in the art, such as water. In addition to such inert diluents, the compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweeteners, flavoring and aromatic agents.

Parenteral formulations of the present invention include, but are not limited to, sterile aqueous or non-aqueous solutions, suspensions, emulsions, and the like. Examples of non-aqueous solvents or carriers include propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin, and suitable injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants, such as preservatives, moisturizing, emulsifying and dispersing agents. They can be sterilized, for example, by filtering the compositions through bacteria-retaining filters, incorporating sterilizing agents into the compositions, treating the compositions with radiation or heating. They can also be made in the form of sterile solid compositions that can be dissolved in sterile water or some other sterile medium for injection, immediately before use.

Compositions for rectal or vaginal administration are preferably suppositories, which may contain, in addition to the active substance, auxiliary substances, such as cocoa butter or suppository wax.

Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.

In addition, the compound of the present invention can be incorporated into sustained release compositions, such as those described in the following patents and patent applications. US Pat. No. 5,672,659 describes sustained release compositions containing a biologically active agent and a polyester. US Pat. No. 5,595,760 describes sustained release compositions containing a biologically active agent in a gelling form. US Pat. No. 5,821,221 describes sustained release polymer compositions containing a biologically active agent and chitosan. US Pat. No. 5,916,883 describes sustained release compositions containing a biologically active agent and cyclodextrin. PCT publication UO 99/38536 describes the easily absorbable sustained release formulations of a biologically active agent. In the PCT

- 27 020613 publication \ νϋ 00/04916 describes a method for the manufacture of microparticles containing a therapeutic agent, such as a peptide, in an oil-in-water system. PCT publication νΟ 00/09166 describes complexes containing a therapeutic agent, such as a peptide, and a phosphorylated polymer. PCT publication νθ 00/25826 describes complexes containing a therapeutic agent, such as a peptide, and a polymer bearing a non-polymerizable lactone.

Unless otherwise specified, all technical and scientific terms used in the present description have the same meaning as they are understood by the average specialist in the field to which the invention belongs. In addition, all publications, patent applications, patents, and other references mentioned herein are hereby incorporated by reference in their entirety.

Claims (22)

CLAIM 1. The compound of formula (I) Χ-Β ¹ -Β ² -Β ³ -Β ⁴ -Β (X) in which X is a cytotoxic or cytostatic agent; In ¹ represents gu (amino acid); each of B ² , B ³ and B ⁴ , independently for each case, represents (Ios) _t , (Aera) _n or -Ο (Θ) -ν ¹ -ν ² -ν ³ -ν ⁴ -ν ⁵ -Ο (Θ) - or absent; Ζ is an analogue of ΗΝΡΥ. corresponding to the formula A ² A ³ -A ⁴ -A ⁵ -A ⁶ -A ⁷ Αθ Α ⁹ A ^ ² A ^ A ^^ ^- A ^ ^7- Α ^ θ ^- A ^^ ^- (ЗОО ΙΕ N0: 2), in which And ¹ represents Tug or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο); And ² represents Rgo; And ³ represents §eg, AF or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο); And ⁴ represents Luke or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο); And ⁵ represents Rgo; A ⁶ is Acre, AF, or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο); A ⁷ represents Akp, AF, or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο); A ⁸ represents Rgo; A ⁹ represents O1y, AF or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο); And ¹⁰ represents O1, AF or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο); A ¹¹ represents Acre, AB or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο); A ¹² is A1a, AF, or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο); A ¹³ represents Rgo; A ¹⁴ is A1a, AF, or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο); A ¹⁵ represents O1, AF or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο); A ¹⁶ represents Acre, AB or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο); A ¹⁷ is Me1, A6c, AF, Me or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο); A ¹⁸ is A1a, AF, or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο); And ¹⁹ represents Agd or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο); And ²⁰ represents Tug or ΗΝ-ΟΗ (ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο); A ²¹ represents Tug or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο); A ²² represents §eg, AF or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο); A ²³ represents A1a, AF, or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο); A ²⁴ represents Ley, A6c or ΗΝ-ΟΗ ((ΟΗ ₂ ) η-Ν (Κ ² Κ ³ )) - Ο (Ο); A ²⁵ represents Agd or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο); A ²⁶ represents Shk or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο); A ²⁷ represents Tug or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο); A ²⁸ is 11e, A6c or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) Ο (Ο); A ²⁹ represents Akp, AB or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο); And ³⁰ represents Ley, A6c or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο); A ³¹ represents 11e, Ley or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο); A ³² represents Tb, AB or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Θ); A ³³ represents Arg, bAgd or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Θ); A ³⁴ is 4Nur; A ³⁵ is Agd, Ac, Ars, Luk, 4XI ₂ Pb, 4XI2CI2Pb or ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Θ); A ³⁶ is Tug, Ac, ΗΝ-ΟΗΑΟΜΧρΜΚΜ'ρ-ΟΥΟ) or is absent; And ³⁷ represents ΗΝ-ΟΗ ((ΟΗ ₂ ) ₄ -Ν (Κ ² Κ ³ )) - Ο (Ο) or is absent; Κ ¹ represents ΟΗ, ΝΗ2, (C1-30) alkoxy or ΝΗ-Χ ⁶ -ΟΗ2-Χ ⁷ , where X ⁶ represents - 28,020,613 (C1 _-40 ) alkyl or (C _2-40 ) alkenyl and X ⁷ represents H, OH, CO2H or C (O) -XH2; each of V ¹ and V ⁵ , independently for each case, represents SC ⁴ K ⁵ ; each of K ⁴ and K ⁵ , independently for each case, is H, P, Br, C1, I, (C1-30) alkyl, (C _2-30 ) alkenyl, substituted (C _{! -30} ) alkyl, substituted (C _2-30 ) alkenyl, 8K ⁶ , 8 (O) K ⁷ or 8 (O) ₂ K ⁸ or K ⁴ and K ⁵ together form (C3-30) cycloalkyl, (C3-30) heterocyclic or (C5- 30) an aryl ring; each of K ⁶ , K ⁷ and K ⁸ , independently for each case, is (C1 _-30 ) alkyl, (C _2-30 ) alkenyl, substituted (C1 _-30 ) alkyl or substituted (C _2-30 ) alkenyl; each of V ² , V ³ and V ⁴ , independently for each case, represents SC ⁹ K ¹⁰ , O, 8, (CH ₂ ), or absent; each of K ⁹ and K ¹⁰ , independently for each case, is H, P, Br, C1, I, (C1 _-30 ) alkyl, (C _2-30 ) alkenyl, substituted (C1 _-30 ) alkyl, substituted ( C _2-30 ) alkenyl, 8K 8 (O) K ⁷ or 8 (O) ₂ K ⁸ or K ⁹ and K ¹⁰ together form a ring system; t, independently for each case, is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n, independently for each case, is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; c |, independently for each case, represents 0, 1, 2, 3, 4 or 5; ΐ, independently for each case, represents 0, 1, 2 or 3; each of K ² and K ³ , independently for each case, is H, (C1 _-40 ) alkyl, (C1 _-40 ) heteroalkyl, (C _{! -40} ) acyl, (C _2-40 ) alkenyl, (C _{2 -40} ) alkynyl, aryl (C1 _-40 ) alkyl, aryl (C _{! -40} ) acyl, substituted (C _{! -40} ) alkyl, substituted (C1 _-40 ) heteroalkyl, substituted (C _{! -40} ) acyl, substituted ( C _2-40 ) alkenyl, substituted (C _2-40 ) alkynyl, substituted aryl (C1 _-40 ) alkyl, substituted aryl (C _{! -40} ) acyl, (C1 _-40 ) alkylsulfonyl or C (XN) -YN ₂ , wherein when K ² is (C1-40) acyl, aryl (C1-40) acyl, substituted (C1-40) acyl, substituted aryl (C1-40) acyl, (C1-40) alkylsulfonyl or C (XN) - YN2, K ³ represents oboj H or (S1-40) alkyl, (C1 _-40) heteroalkyl, (C _2-40) alkenyl, (C _2-40) alkynyl, aryl (C 1 _-40) alkyl, substituted (S1-40) alkyl substituted (C1-40) heteroalkyl, substituted (C2-40) alkenyl, substituted ( _C2-40 ) alkynyl or substituted aryl ( _C1-40 ) alkyl; or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, in which X is anthracycline, camptothecin or a camptothecin derivative, paclitaxel or a paclitaxel derivative or doxorubicin or a doxorubicin derivative; B ¹ represents guAcr, ΓνΌ-Acre, gCuA, ΓνΌ-Cba or gOO1y; B ² is 8is; each of B ³ and B ⁴ , independently for each case, is (OOS) _t , (Aera) _n or absent; K ¹ represents NH ₂ ; each of K ² and K ³ , independently for each case, is H or (C1-30) acyl; with the proviso that when K ² is (C1-30) acyl, K ³ is H; each of K ⁴ and K ⁵ , independently for each case, is H or (C1 _-40 ) acyl; with. | represents 4; and each of X ¹ , X ² , X ³ , X ⁴ and X ⁵ , independently for each case, is H, CH ₂ XH ₂ or ΝΉ ₂ or a pharmaceutically acceptable salt thereof. 3. The compound of claim 2, wherein X is anthracycline, or a pharmaceutically acceptable salt thereof. 4. The compound of claim 2, wherein X is camptothecin or a camptothecin derivative, wherein said camptothecin derivative is - 29,020,613 or a pharmaceutically acceptable salt thereof. 5. The compound of claim 2, wherein X is paclitaxel or a paclitaxel derivative, wherein said paclitaxel derivative is or a pharmaceutically acceptable salt thereof. 6. The compound of claim 2, wherein X is doxorubicin or a doxorubicin derivative, wherein said doxorubicin derivative is - 30,020,613 or a pharmaceutically acceptable salt thereof. 7. The compound according to any one of claims 2 to 6, in which A ¹ represents Tug; A ³ is Zeg; And ⁴ represents Luke; A ⁶ is Acre; A ⁷ is Akp; A ⁹ is C1u; A ¹⁰ is C1i; A ¹¹ represents Acre; A ¹² is A1a; A ¹⁴ is A1a; A ¹⁵ is C1i; A ¹⁶ represents Acre; A ¹⁷ is AB or Me; A ¹⁸ is A1a; A ¹⁹ represents Agd; A ²⁰ is Tug; A ²¹ represents Tug; A ²² is Zeg; A ²³ represents A1a; A ²⁴ represents Ley; A ²⁵ represents Agd; A ²⁶ is Shk; A ²⁷ is Tug; A ²⁸ is 11e; A ²⁹ represents Akp; A ³⁰ is lei; A ³¹ represents 11e or Abs; A ³² is Tb; A ³³ represents Agd; A ³⁵ is Agd or Ac; A ³⁶ is Tug, Ac or absent; A ^{37 is} absent, or a pharmaceutically acceptable salt thereof. 8. The compound according to claim 7, in which X is camptothecin, or a pharmaceutically acceptable salt thereof. 9. The compound of claim 8, where the specified connection is a - 31 020613 [camptothecin-guAzr-Zis-Tug ¹ , Νίβ ¹⁷ , 4Nur ³⁴ ] ΙϊΝΡΥ (1-36) -ΝΗ ₂ (ZEO 1B ΝΟ: 89); [camptothecin-chl / B-Azr-Zis-Tug ¹ , Νίβ ¹⁷ , 4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ2; [camptothecin-chl / Azr-Zis-Tukh · ¹ , Ν1θ ¹⁷ , Abs ³¹ , 4Nur ³⁴ ] ΗΝΡΥ (136) -ΝΗ2 (ZEO Ιϋ N0: 90); [camptothecin-hllB-Azr-Zis-Tukh · ¹ , Νίβ ¹⁷ , Abs ³¹ , 4 Nur ³⁴ ] ΗΝΡΥ (136) -ΝΗ ₂ ; [camptothecin-glsSZ-u-Zis-Tug ¹ , Νίβ ¹⁷ , Abs ³¹ , 4 Nur ³⁴ ] ΗΝΡΥ (136) -ΝΗ ₂ (ZEO Yu N0: 91); [camptothecin-x ^ ОХу-Зис-Туг ¹ , Νίβ ¹⁷ , 4Nur ³⁴ ] ΕΝΡΥ (1-36) -ΝΗ ₂ (ЗЕО Ιϋ N0: 94); [camptothecin-gmC1u-Zis- (Όοσ) s-Tug ¹ , Νίβ ¹⁷ , 4Nur ³⁴ ] ΙϊΝΡΥ (136) -ΝΗ ₂ (ZEO ΙΌ N0: 95); [camptothecin-gm <31u-3is- (Ros) s-Aera-Tug ¹ , Νίβ ¹⁷ , 4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ ₂ (Zeo Yu N0: 96); [camptothecin-gmAzr-Zis- (Bos) s-Tug ¹ , Ν1θ ¹⁷ , 4Nur ³⁴ ] ΕΝΡΥ (136) -ΝΗ ₂ (ZEO Ιϋ N0: 97); [camptothecin-gmB-Azr-Zis- (Bos) s-Tug ¹ , Νΐθ ¹⁷ , 4 Nur ^{3 4} ] ΙϊΝΡΥ (136) -ΝΗ ₂ ; [camptothecin-gmO1y-Zis-Aera- (Bos) s-Tug ¹ , Νίβ ¹⁷ , 4Nur ³⁴ ] ΙϊΝΡΥ (1-36) -ΝΗ ₂ (ZEO ΙΒ N0: 98); [camptothecin-chl / Azr-Zis- (Bos) s-Aera-Tug ¹ , Νίβ ¹⁷ , 4Nur ³⁴ ] ΙϊΝΡΥ (1-36) -ΝΗ ₂ (ZEO Ιϋ N0: 99); [camptothecin-gmB-Azr-Zis- (Bos) ₃ -Aera-Tug ¹ -I1e ¹⁷ , 4Nur ³⁴ ] ΙϊΝΡΥ (1-36) -ΝΗ ₂ ; [camptothecin-chl / Azr-Zis-Aera- (Bos) s-Tug ¹ , Νίβ ¹⁷ , 4Nur ³⁴ ] ΙϊΝΡΥ (1-36) -ΝΗ ₂ (ZEO 1B N0: SO); [camptothecin-gmB-Azr-Zis-Aera- (Bos) s-Tug ¹ , Νΐθ ¹⁷ , 4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ ₂ ; [camptothecin-guCNu-Zis-Tug ¹ , Arb ¹⁷ , 4 Nur ³⁴ , Αίο ³⁶ ] ΙϊΝΡΥ (136) -ΝΗ ₂ (Zeo Yu N0: 101); [camptothecin-guSNu-Zis-Tug ¹ , Arb ¹⁷ , 4 Nur ³⁴ , Ags ³⁵ ] ΙϊΝΡΥ (135) -ΝΗ ₂ (ZEO 1B N0: 102); [camptothecin-gmC51y-Zis- (Bos) s-Tug ¹ , Arb ¹⁷ , 4 Nur ³⁴ , Ags ³⁶ ] ΗΝΡΥ (1-36) -TH ₂ (ZEO ΠΟΝΟ: 103); [camptothecin-gmC1y-Zis-Aera- (Bos) ₃ Tug ¹ , Arb ¹⁷ , 4 Nur ³⁴ , Ags ³⁶ ] LIU (1-Zb) -ΝΗ ₂ (ZEO Ιϋ ΝΟ: 104); [ЗпЗв-ГУАзр-Зис-Туг ¹ , Νΐθ ¹⁷ , 4Nur ³⁴ ] ΙϊΝΡΥ (1-36) -IN ₂ (ЗОО 1Б N0: 89} OR [ЗпЗЗ-гмАзр-Зис-Туг ¹ , Νίβ ¹⁷ , Abs ³¹ , 4Ηγρ ³⁴ ] 1τΝΡΥ (1-36) -ΝΗ ₂ (ZEO 1P N0: 90) or a pharmaceutically acceptable salt thereof. 10. A mixture containing [camptothecin-guA8p-5is-Tug ¹ , Ly1e ¹⁷ , 4Nur ³⁴ ] LKRU (1-36) -NY2 (8E9 GO LyO: 89) and [camptothecin-guP-A8p-8is-Tyg ¹ , Me ¹⁷ , 4 Nur ³⁴ ] LKRU (1-36) -KH2, or its pharmaceutically acceptable salt. 11. A mixture containing [camptothecin-guA8p-5is-Tug ¹ , Me ¹⁷ , A6c ³¹ , 4Nur ³⁴ ] LKRU (1-36) -KH2 (8E9 GO ΝΌ: 90) and [campothecin-gu0-A8p-5is-Tug ¹ , Me ¹⁷ , A6c ³¹ , 4Nur ³⁴ ] LKRU (1-36) -KH2, or a pharmaceutically acceptable salt thereof. 12. A mixture according to any one of paragraphs.10, 11, containing a ratio (weight: weight) of about 2:98, about 5:95, about 10:90, about 15:85, about 20:80, about 25:75 , about 30:70, about 35:65, about 40:60, about 45:50, about 50:50, about 55:45, about 60:40, about 65:25, about 70:30, about 75:25 , about 80:20, about 85:15, about 87:13, about 88:12, about 90:10, about 95: 5, about 97: 3, or about 98: 2 of the specified pair of compounds, or - 32,020,613 pharmaceutically acceptable salt. 13. The compound according to claim 1, in which Ζ corresponds to: [ΑΪΗ ¹⁰ , 4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ2 (ЗЕО ЮЮ N0: 3); [ΑίΗ ¹⁷ , 4Nur ³⁴ ] ΗΝΡΥ (1-3 6) -ΝΗ2 (ЗЕО 1ЮИ0: 4); [ΑίΗ ¹¹ · ¹⁷ , 4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ2 (ZEO Ιϋ N0: 5) [4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ2 (ZEO Ιϋ N0: 6); [ΑίΗ ²² , 4Ηγρ ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ2 (ЗЕО 1Ю N0: 7); [A6C ³¹ , 4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ2 ZEO Ιϋ N0: 8); (Abs ³⁰ , 4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ2 (ZEO GON0: 9); [Abs ²⁸ , 4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ2 (ZEO UI: 10) [ΑίΗ ³ , 4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ ₂ (ЗЕО 1ЮЫ0: 11); [A6C ²⁴ , '4Nur * ⁴ ] ΙϊΝΡΥ (1-36) -ΝΗ ₂ (3Ε0 1st N0: 12) [ΑίΗ ⁶ , 4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ ₂ (3Ε0 1st N0: 13); [ΑίΗ ¹⁸ , 4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ ₂ (3Ε0 1st N0: 14) [ΑίΗ ²⁹ , 4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ ₂ (3Ε0 1st N0: 15) [Ar ³² , 4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ ₂ (3Ε0 1st N0: 16) [ΑίΗ ²³ , 4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ ₂ (5Ε0 1st ΝΟ: 17) [Abs ¹⁷ , 4Ηγρ ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ ₂ (3Ε0 1st N0: 18) [ΑίΗ ¹¹ , 4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ ₂ (3Ε0 ΐϋ N0: 19) [ΑίΗ ¹² , 4Ηγρ ³¹ ] ΗΝΡΥ <1-36) -ΝΗ ₂ (3Ε0 1st N0: 20); [ΑίΗ ¹⁴ , 4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ ₂ (3Ε0 1st N0: 21); [ΑίΗ ¹⁵ , 4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ ₂ (BEO Ιϋ N0: 22); [ΑίΗ ¹⁶ , 4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ ₂ (3Ε0 1st N0: 23); [ΑίΗ ⁷ , 4 Nur ³⁴ [ΗΝΡΥ (1-36) -ΝΗ ₂ (ZEO ΙΏ N0: 24); [ΑίΗ ⁵ , 4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ ₂ (ЗЕО 1Ю N0: 25); [ΑίΗ ^{10 '17, 34} 4Nur] ΗΝΡΥ (1-36) -ΝΗ ₂ (ZEO Yu N0: 26); [ΑίΗ ¹⁵ · ¹⁷ , 4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ ₂ (ЗЕО Ш N0: 27); [ΑίΗ ¹¹ · ¹⁵ , Νίβ ¹⁷ , 4 Nur ³⁴ ] ΗΝΡΥ (1-36> -IN ₂ (ZEO 1UI0: 28); [ΑίΗ ^{10 '15, 17} Y1e, 4Nur ^34] ΗΝΡΥ (1-36) -ΝΗ ₂ (ZEO Yu N0: 29); [ΑίΗ ^{11,15 '17, 34} 4Nur] ΙϊΝΡΥ (1-36) -ΝΗ ₂ (ZEO 1yu N0: 30); [ΑίΗ ¹² ' ¹⁵ ' ¹⁷ , 4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ ₂ (ZEO 1BIO: 31); [ΑίΗ ¹⁰ ' ¹⁵ ' ¹⁷ , 4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ ₂ (ZEO ΙϋΝ0: 32); [ΑίΗ ^11.15 , 4Nur ³⁴ ] ΙϊΝΡΥ (1-36) -ΝΗ ₂ (ZEO ΙΏΝΟ: 33); [ΑίΗ ¹⁰ · ¹⁶ , 4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ ₂ (ЗЕО ЕУ Н0: 34); [ΑίΗ ¹⁷ , 4Nur ³⁴ , Ars ³⁵ ] ΗΝΡΥ (1-36) -ΝΗ ₂ (ZEO ΙΠΝΟ: 36); [ΑίΗ ¹⁷ , 4 Nur ³⁴ , Ahs ³⁶ ] ΗΝΡΥ (1-36) -ΝΗ ₂ (ZEO ΙΒ N0: 37); [ΑίΗ ¹⁷ , 4Nur ³⁴ , 4ΝΗ2ΡΗβ ³⁵ ] ΗΝΡΥ (1-36) -ΝΗ2 (ЗЕО 1Ю N0; 38); [ΑίΗ ¹⁷ , 4Nur ³⁴ , 4НН2СН2РНе ³⁵ ] ΗΝΡΥ (1 - 36) -ΝΗ2 (5Е0 Ιϋ N0: 39); or a pharmaceutically acceptable salt thereof. 14. The compound according to claim 2, in which A ^{37 is} absent, or a pharmaceutically acceptable salt thereof. 15. The compound according to 14, in which Ζ corresponds to: [ΑίΗ ¹⁰ , 4Nur ³⁴ ] ΙϊΝΡΥ (1-36) -ΝΗ ₂ (ЗЕО ЮЮ N0: 3); [ΑίΗ ¹⁷ , 4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ ₂ (ЗЕО 1ЮЫО: 4); [ΑίΗ ^11.17 , 4 Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ ₂ (ЗЕ0 1ЫЫО; 5); [4Nur ³⁴ ] ΗΝΡΥ (1-36) -ΝΗ ₂ (ЗЕО П> НО: 6); - 33,020,613 [ΑίΒ ²² , '4Nur ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ ₂ (3Ε0 Ιϋ N0: 7); [Abs ³¹ , 4Nur ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ ₂ zeo: Ιϋ N0: 8); [Abs ³⁰ , 4Nur ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ ₂ (3Ε0 YU N0: 9); [Abs ²⁸ , 4Nur ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ ₂ (5Ε0 ΙΟ N0: 10) [ΑίΒ ³ , 4Nur ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ ₂ (3Ε0 Ιϋ N0: 11); [Abs ²⁴ , 4Nur ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ ₂ (5Ε0 Ιϋ N0: 12) [ΑίΒ ⁶ , 4Nur ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ ₂ (3Ε0 Ιϋ N0: 13), [ΑίΒ ¹⁸ , 4Nur ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ ₂ (3Ε0 YU N0: 14) [ΑίΒ ²⁹ , 4Nur ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ ₂ (3Ε0 YU N0: 15) [ΑίΒ ³² , 4Nur ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ ₂ (3Ε0 Ιϋ N0: 16) [ΑίΒ ²³ , 4Nur ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ ₂ (3Ε0 YU N0: 17) [Abs ¹⁷ , 4Nur ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ ₂ (3Ε0 YU N0: 18) [ΑίΒ ¹¹ , 4Nur ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ ₂ (3Ε0 YU N0: 19) [ΑίΒ ¹² , 4Nur ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ ₂ (3Ε0 YU N0: 20), - [ΑίΒ ¹⁴ , 4Nur ³⁴ ] ΒΝΡΥ (1 - 3 6) -ΝΗ ₂ (3Ε0 Ιϋ N0: 21); [ΑίΒ ¹⁵ , 4Nur ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ ₂ (3Ε0 Yu N0: 22); [ΑίΒ ¹⁶ , 4Nur ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ ₂ (3Ε0 YU N0: 23); [ΑίΒ ⁷ , 4Nur ³⁴ ] ΒΝΡΥΐΙ-36) -ΝΗ ₂ (3Ε0 Ιϋ N0: 24); [ΑίΒ ⁹ , 4Nur ³⁴ ] ΒΝΕΥ (1-36) -ΝΗ ₂ (3Ε0 Ιϋ N0: 25); [ΑίΒ ^10.17 , 4Ηγρ ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ ₂ (ZEO ΙΟΝΟ: 26); [ΑίΒ ^{15 '17, 34} 4Nur] ΒΝΡΥ (1-36) -YN ₂ (W 8ES uQ 27!); [ΑίΒ ^11.16 , Νίβ ¹⁷ , 4 Nur ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ ₂ (ZEO W N0: 28); [ΑίΒ ^{10 '15,} Νΐε ¹⁷ 4Nur ^34] ΒΝΡΥ (1-36) -ΝΗ ₂ (ZEO Yu N0: 29); [ΑίΒ ¹¹ ' ¹⁵ ' ¹⁷ , 4Nur ³⁴ ] ΒΝΡΥ (1-36) -TH ₂ (ZEO Ιϋ N0: 30); [ΑίΒ ¹² ' ¹⁵ ' ¹⁷ , 4Nur ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ ₂ (ZEO ΙϋΝ0: 31); [ΑίΒ ¹⁰ ' ¹⁵ ' ¹⁷ , 4Nur ³⁴ ] ΒΝΡΥ (1-36) -ΝΗ ₂ (ZEO 1ZIO: 32); [ΑίΒ ^{11 '16, 34} 4Nur] ΒΝΡΥ (1-36) -ΝΗ ₂ (ZEO Yu N0: 33); [ΑίΒ ^{10 '16, 34} 4Nur] ΒΝΡΥ (1-36) -ΝΗ ₂ (ZEO Εϋ N0: 34); [ΑίΒ ¹⁷ , 4Nur ³⁴ , Ars ³⁵ ] ΒΝΡΥ (1-36) -YN ₂ (ZEO 1PYO: 36); [ΑίΒ ¹⁷ , 4Nur ³⁴ , Αίθ ³⁶ ] ΒΝΡΥ (1-36) -ΝΗ ₂ (ЗЕО Ш N0: 37); [ΑίΒ ¹⁷ , 4Nur ³⁴ , 4ΝΗ2ΡΒβ ³⁵ ] ΒΝΡΥ (1-36) -НН2 (ЗОО ΙϋΝΟ: 38) or [ΑίΒ ¹⁷ , 4Nur ³⁴ , 4ΝΗ2ΟΗ2ΡΒ0 ³⁵ ] ΒΝΡΥ (1-36) -ΝΗ2 (ЗЕО Ιϋ N0: 39) or a pharmaceutically acceptable salt thereof. 16. The compound according to claim 1 or 2, in which the peptide bond between A ³⁵ and A ^{36 is} replaced by a pseudo peptide bond, or a pharmaceutically acceptable salt thereof. 17. The compound according to clause 16, in which A ³⁵ -A ³⁶ represents Luc ^ (CH ₂ -MN) Tug or Luc ^ (CH ₂ - ^ Ac)) Tug, or its pharmaceutically acceptable salt. 18. The compound of claim 17, wherein Ζ corresponds [ΑίΒ ^{11 '17, 34} 4Nur, uz ³⁵ ip (CH2 N (Ac)) Tyr ^36] ΒΝΡΥ (1-36) -ΝΗ2 (ZEO ΙΏ N0: 35 ); [ΑίΒ ¹⁷ , 4Nur ³⁴ , L3- ^{, g} '- (CH ₂ -HH) Tug ³⁵ ] ΗΗΡΥ (1-36) -ΝΗ- · (ZEO I) BUT: 40) or [ΑίΒ ¹¹ ' ¹⁷ , 4Nur ³⁴ , Tsue ³⁵ -f (ΟΗ2-ΝΗ) Tug ³⁶ ] ΒΝΡΥ (1-36) -ΝΗ2 (ZEO ΙϋΝ0: 41), or a pharmaceutically acceptable salt thereof. 19. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 9 and 13-18, a mixture according to any one of claims 10 to 11, or a pharmaceutically acceptable salt thereof. 20. The pharmaceutical composition according to claim 19, further comprising a pharmaceutically acceptable carrier. 21. A method of treating a disease in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound according to any one of claims 1 to 9 and 13-18, a mixture according to any one of claims 10 to 11, or a pharmaceutically acceptable composition according to claim 19 or 20, wherein said disease is characterized by impaired or undesired proliferation of cells expressing the receptor YARU-UE 22. A method of treating a disease in a subject in need of claim 21, wherein said disease is selected from the group consisting of breast cancer, ovarian cancer, glial tumors, renal cell carcinomas, nephroblastoma, and intratumoral blood vessels.